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A 

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THE PREVENTION OF 
RESPIRATORY TRACT 
BACTERIAL INFECTIONS T 
BY SULFADIAZINE 
PROPHYLAXIS IN ' 

THE UNITED STATES NAVY 



BUREAU OF MEDICINE AND SURGERY 
NAVY DEPARTMENT, WASHINGTON, D. C. 



THE PREVENTION OF RESPIRATORY TRACT 
BACTERIAL INFECTIONS BY SULFADIAZINE 
PROPHYLAXIS IN THE UNITED STATES NAVY 


NAVMED 284 

MS, bureau of medicine and surgery 

' NAVY DEPARTMENT, WASHINGTON, D. C. 





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Introduction 

Captain T. J. Carter (MC) U.S.N. 

In Charge, Division of Preventive Medicine 

Bureau of Medicine and Surgery 

Navy Department, Washington, D. C. 

E xperience with streptococcal diseases during 1942-1943 made imperative 
a program for prevention and control in the Navy. The incidence of 
scarlet fever, tonsillitis, and pharyngitis was high. Rheumatic fever, with 
its debilitating sequelae and concomitant disabling effects, increased the 
alarming loss in manpower and fighting strength. That there was a 
problem and that action was indicated were indisputable. The opinions 
as to what should be done, however, varied with the medical officers ex¬ 
pressing them, in accordance with the variety of their experiences with 
streptococcal disease. 

On 7 September 1943 a group of medical officers convened at the Bu¬ 
reau of Medicine and Surgery to explore the entire problem thoroughly. 
These officers were experienced in preventive medicine, both within the 
Navy and prior to Naval Service, in civilian life. The concensus was 
that the problem could be attacked from two standpoints, control and 
study. The prime objective would be to reduce the incidence of strep¬ 
tococcal diseases and consequently the time-loss. Control efforts could 
certainly be utilized to aid in delineating more clearly the true nature of 
the problem and point the way to its solution. It was felt that whatever 
the means of control, it was essential that developments should be kept 
under scrutiny by trained investigators, to the end that full advantage 
might be taken of both successes and shortcomings. After a thorough 
exploration of the means at hand and consideration of the desirability and 
practicability of the several control studies proposed, the conference con¬ 
cluded that sulfadiazine prophylaxis would provide the most feasible ap¬ 
proach and the maximum benefit to the Navy. 

Commander Alvin F. Coburn, MC-V(S), U.S.N.R., nationally known 
authority on streptococcal diseases, was selected to organize the program 
and tb set it in operation. Supplementary to field administration of the 
project, it was necessary to establish a streptococcal typing laboratory and 


V 


to provide adequately trained personnel. Fortunately, Lieutenant Com¬ 
mander Armine T. Wilson, MC-V(S), U.S.N.R., formerly of the Rocke¬ 
feller Institute, was available for this purpose. 

A preliminary survey of six of our larger Naval activities was imme- 
mediately undertaken, and arrangements were completed to place the pro¬ 
gram in operation under supervision of the epidemiology units already 
assigned. Administrative problems were rapidly solved, and on 15 De¬ 
cember 1943 the program was well under way at these major establish¬ 
ments. Programs of less magnitude were authorized from time to time. 

The complete story of the sulfadiazine prophylaxis program as it was 
carried out at each of the Naval activities is presented in the following 
pages of this monograph, together with a summary of the total program 
and a consideration of its implications. This project, it is believed, is the 
largest controlled investigative study ever undertaken and is marked by 
productive results and guideposts which will surely find their way into 
the history of preventive medicine. Inevitably, development was troubled 
by errors, although little time was lost in their correction. 

Earnest tribute is due the officers and men and women of the epidem¬ 
iology units who carried so much of the responsibility of this program. 
For them a round-the-clock schedule was not too much in order to insure 
that each patient was fully cared for and that all the investigative elements 
were fully considered. Their loyalty and interest were exemplary. 

Finally, the man who had the courage, the point of view, and the deter¬ 
mination to carry on was Vice Admiral Ross T Mclntire (MC), U.S.N., 
Surgeon General of the United States Navy and Chief of the Bureau of 
Medicine and Surgery. His judicious counsel and encouragement, as 
well as that of Rear Admiral Luther Sheldon, Jr. (MC), U.S.N., Assist¬ 
ant Chief of the Bureau, supported us steadily in this practical application 
of preventive medicine. 


vi 


Report 1 

The Grouping and Typing of 
Beta Hemolytic Streptococci 

From the Streptococcus Typing Laboratory, Epidemiology Unit 100* 
National Naval Medical Center^ Bethesda, Md. 

The serologic identification of strains of bacteria is useful in studying the 
spread of epidemic infectious disease. In the case of beta hemolytic 
streptococcal infections, the strains are first assigned to the group to which 
they belong, and if they are members of group A (Lancefield), they are 
further differentiated according to their types within group A. 

When the current sulfadiazine prophylaxis program was initiated in 
the Navy, a streptococcal typing laboratory was established at the Naval 
Medical School, National Naval Medical Center, Bethesda, Md., and 
strains were sent to that laboratory from the various activities partici¬ 
pating in the program, for serologic identification. This report presents 
the basis of serologic grouping and typing and a brief account of the 
methods employed. The use made of the grouping and typing data sup¬ 
plied by the laboratory is presented in detail in the succeeding reports 
of this epidemiology symposium. 

Grouping 

For the purposes of this investigation, interest was restricted to group 
A beta hemolytic streptococci, because members of that group are respon¬ 
sible for almost all hemolytic streptococcal respiratory illness in man. 
By means of a potent and specific absorbed group A serum, it was possible 
to test for membership in group A alone, and, on the basis of reaction 
or absence of reaction with that serum, to assign a strain to group A, or 
to say that it did not belong to group A. Strains that were not members 
of group A were not further identified. 

♦Participant: Armine T. Wilson, Lieutenant Commander (MC) USNR. 
Assistants: George Prentice, Chief Pharmacist’s Mate; Harold Elwyn, PhMlc, 
USNR; Isabel Erskine, PhM2c, USNR; Hulda Hobbs, PhM2c, USNR. 


I 



The Basis of Typing 

There are two methods of typing group A streptococci in current use: 
One is the slide agglutination method of Griffith \ the other is the 
precipitin technic of Lancefield as modified for use in capillary tubes (2). 
From an epidemiologic point of view, it matters little which method is 
used to determine the type of strain so long as the same method is used 
for all the material to be treated in one analysis. It should be understood 
that the results of the two methods are not always in agreement, because, 
in certain instances, they measure diflFerent antigenic components of the 
organism. 

Hemolytic streptococci of group A have two type-specific antigens, 
known as M and T. In precipitin typing, only the M antigen or M sub¬ 
stance is involved. The M antigen is protein in nature and is extractable 
from the cell into solution by acid. When such a cell-free extract is 
neutralized and placed in contact with an anti-M containing serum pre¬ 
pared from a strain of the same type, a precipitin reaction occurs. With 
serums prepared from other types, no such reaction occurs, provided the 
serums have had their group and non-type-specific antibodies removed 
by absorption. 

The method of precipitin typing, then, consists of placing an acid ex¬ 
tract of an unknown strain in contact with the absorbed anti-M serums 
of all known types. The type with which the extract reacts will be the 
type of the strain. 

In the intact cell the M substance usually, although not always, parti¬ 
cipates in an agglutination reaction when a suspension of cells is added 
to an anti-M containing serum of the same type. The antibodies to the 
M substance are also responsible for the type-specific immunity that an 
animal acquires when actively or passively immunized. 

The T antigen, on the other hand, has not yet been identified chemi¬ 
cally nor can it be demonstrated outside of the cell. Its presence is rec¬ 
ognized only by agglutination of the intact cell in the corresponding anti-T 
serum. So far as is known, it is never involved in a precipitin reaction, 
and it does not influence the immunity of the animal to infection. 

It can be seen that whereas the precipitin typing method depends entire¬ 
ly on the reaction of the M substance of the organism with its correspond¬ 
ing antibodies, the slide agglutination typing method may involve the M 
substance and its antibody, or the T antigen and its antibody, or both. If 
particular M and T antigens were invariably associated in particular types, 
there would be no reason for confusion in the use of the two tests. This, 
unfortunately, is not the case (i). Some strains are without demon¬ 
strable M substance, although they contain T antigen, and other strains 
are without T, although they contain M. Some strains, which share the 
same M substance and hence will be assigned to the same type on the 
basis of precipitin typing, have T antigens of different types, and will be 

2 


assigned to different types when tested by slide agglutination. Other 
strains with the same or serologically related T antigens have distinct M 
antigens. One strain has been encountered with the M antigen of one 
type, a T antigen of the same type, and an additional T antigen of another 
type. 

For a complete antigenic analysis both precipitin and agglutination 
technics must be employed, serums being used of accurately known anti¬ 
genic composition. The unusual combinations of antigens mentioned are 
not frequent, but occur often enough to make it unsafe to compare epi¬ 
demiologic data based on slide agglutination typing alone with data based 
on precipitin typing alone, and vice versa. For most epidemiologic pur¬ 
poses, however, a single method will suffice, and the choice of method to 
be used in any given investigation will depend on the availability of re¬ 
liable serums and the experience of the typer. 

Methods 

In this investigation the capillary precipitin method of Swift, Wilson 
and Lancefield (2) has been used exclusively. The details of that method 
are given in full in their article, and will be reviewed only briefly here. 
The method was devised in an attempt to make precipitin typing practi¬ 
cable in large-scale typing enterprises, and the essential advantage which 
it possesses over commonly used precipitin tests lies in the conservation 
of materials made possible by the use of capillary types in which to develop 
the reaction. The serums used in capillary typing must be of high 
potency and specificity, and we were fortunate in obtaining ample supplies 
of such serums through the generosity of Doctors Homer F. Swift and 
Rebecca C. Lancefield of the Hospital of the Rockefeller Institute for 
Medical Research. 

Precipitin testing in capillaries is accomplished by drawing a small 
amount of serum into the capillary tube by capillary attraction, and then 
drawing an approximately equal amount of extract into the tube, without 
allowing an air bubble to separate the two liquids. Depending on the 
strength of the serums used, the precipitate appears immediately, or after 
2 hours’ incubation at 37® C., or after having been kept overnight in the 
icebox. 

Strains were sent from the field tO' the Bethesda laboratory as soon as 
possible after isolation. They were stored in the icebox until ready for 
study. They were then tested for pure culture and were grown in 40 cc. 
of tryptose phosphate broth, fortified with 0.5 percent normal horse serum 
or rabbit serum. The organisms obtained from such cultures were ex¬ 
tracted with hydrochloric acid. After the extract was neutralized, it 
was ready for grouping and typing, the same extract being used for the 
two procedures. 


3 


It was discovered early that most of the strains which were ultimately 
typed fell into ten common types: 1, 3, 5, 6, 12, 17, 18, 19, 24, and 30. 
For this reason it was decided to set up the extracts first with these ten 
serums. If the strain did not belong to one of these types, it was then 
set up with the other typing serums. At one station (Farragut) the ma¬ 
jority of strains belonged to types 1, 17 and 19, and a further reduction 
in initial typing was possible in that instance. These screening proced¬ 
ures resulted in a significant saving of time, serums, and capillaries. 

Serums were available for 36 of the 40 known types of group A beta 
hemolytic streptococci. In addition to the ten common ones listed, these 
were 2, 4, 8, 9, 11, 13, 14, 15, 22, 23, 26, 28, 29, 31, 32, 33, 36, 37, 38, 39, 
40, 41, 42, 43, 44, and 46. 

Table 1.— Serologic types of hemolytic streptococcus at naval training stations 


Type 

Bainbridge 

Farragut 

Great Lakes 

Sampson 

other 

Activities 

Total 

1 

87 

108 

54 

11 

34 

294 

2 

4 

0 

2 

3 

3 

12 

3 

26 

61 

72 

48 

28 

235 

4 

0 

2 

1 

2 

0 

6 

5 

28 

4 

94 

29 

6 

161 

6 

28 

22 

23 

30 

18 

121 

8 

0 

1 

0 

1 

3 

5 

9 

0 

3 

1 

1 

0 

5 

11 

0 

0 

0 

2 

0 

2 

12 

27 

7 

12 

34 

10 

90 

13 

1 

0 

1 

3 

1 

6 

14 

6 

22 

0 

4 

23 

54 

15 

0 

0 

0 

0 

0 

0 

17 

69 

305 

95 

26 

93 

588 

18 

85 

10 

1 

4 

4 

104 

19 

392 

342 

78 

15 

128 

955 

22 

0 

0 

0 

. 0 

0 

0 

23 

0 

0 

0 

0 

0 

0 

24 

36 

25 

6 

12 

6 

85 

26 

0 

0 

7 

7 

4 

18 

28 

4 

4 

0 

2 

2 

12 

29 

6 

0 

0 

2 

0 

8 

30 

30 

1 

3 

21 

12 

67 

81 

0 

0 

0 

0 

0 

0 

32 

0 

0 

3 

2 

0 

5 

33 

2 

2 

1 

2 

0 

7 

36 

4 

20 

6 

2 

16 

48 

37 

0 

0 

0 

0 

0 

0 

38 

0 

0 

0 

0 

0 

0 

39 

0 

0 

3 

2 

0 

5 

40 

0 

0 

0 

0 

0 

0 

41 

3 

2 

2 

9 

1 

17 

42 

0 

0 

0 

0 

0 

0 

43 

2 

0 

1 

2 

0 

5 

44 

2 

2 

1 

3 

1 

9 

46 

1 

0 

1 

0 

2 

4 

? 

134 

111 

64 

168 

87 

564 

Not group 
A 

258 

135 

104 

394 

178 

1,069 

Total 

1,234 

1,189 

636 

841 

660 

4,560 


4 





















Results 


Table 1 gives an over-all summary of the findings regarding strains on 
which work was completed by 31 May 1944. It can be seen that slightly 
more than 20 percent of the strains submitted were not group A strains; 
83 percent of the group A strains were successfully typed with the serums 
available. High proportions of untypable strains were received from the 
Sampson station and from cultures of a group of healthy carriers at Bain- 
bridge. It is well known that carrier strains are often low in M content; 
hence they are difficult to type by the precipitin method. It is possible, to 
be sure, that some of the failures may have arisen from the presence of 
strains belonging to types for which no serums were available. 

The significance of the distribution of types in relation to the epidem¬ 
iologic conditions in the field is considered in the succeeding reports. 


REFERENCES 

1. Griffith, F. : Serological classification of streptococcus pyogenes. J. Hyg. 
34: 542-584, December 1934. 

2. Swift, H. F. ; Wilson, A. T.; and Lancefield, R. C. : Typing group A hem¬ 
olytic streptococci by M precipitin reactions in capillary pipettes. J. Exper. Med. 
78: 127-133, August 1943. 

3. Lancefield, R. C., et al.: Studies on the antigenic composition of group A hem¬ 
olytic streptococci. J. Exper. Med. 79: 79-114, January 1944. 


5 













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Report 2 

Mass Administration of Sulfadiazine in the 
Prevention of Respiratory Illness 

United States Naval Training Station, Farragut, Idaho 

From Epidemiology Unit 22* 

Soon after the commissioning of this station on 15 September 1942 the 
outstanding epidemiologic fact was the rapid development of a high inci¬ 
dence of respiratory diseases. A high communicable disease incidence 
among unseasoned recruits of training stations is not unusual. The mor¬ 
bidity rate for respiratory tract infections, notably scarlet fever and other 
streptococcal diseases, became consistently higher, however, than that of 
other U. S. Naval Training Stations and persisted throughout 1943. This 
observation is illustrated in chart 1. 

As a result of these infections, severe attacks of rheumatic fever occurred 
in large numbers of personnel stationed at Farragut during the first year, 
and the incidence of this disease increased to an alarming degree early in 
the second year. It was already known that this particular section of the 
Northwest had for years reported one of the highest per capita rates for 
acute rheumatic fever among the civilian population; nevertheless, it ap¬ 
peared that factors other than environment were operating among Naval 
personnel. Among these were the rapid expansion of intensive training 
programs necessitated by urgent military needs, which took precedence 
over health precautions and created overcrowding; and a daily influx of 
raw recruits which constantly furnished new groups of susceptible persons. 

* Participants: Wm. P. Mull, Captain (MC) USN; B. B. Breese, Lieutenant 
Commander (MC) USNR; A. F. Errington, Lieutenant Commander (MC) 
USNR; Walter Stoefeler, Lieutenant Commander (MC) USNR; and Grove G. 
Wiley, Pharmacist USNR. 

The following enlisted personnel assisted in the laboratory, field, and analysis of 
data: Wm. D. Harrison, PhMlc; Edward L. Warmanen, PhMlc; Carl G. Johnson, 
PhMlc; Louis E. Wagshol, PhMlc; Peter Packet, PhM2c; Alfred H .Rodger, 
PhM2c; LeRoy V. Grussendorf, PhM2c; Gene W. Johnston, PhM2c; Fred W. 
Elias, PhM3c. 


7 




tained among all recruits for an initial period of 3 weeks. This assured 
as nearly an ideal control of communicable disease as was possible without 
interfering with the normal training program. Despite these precautions, 
it was soon apparent that the respiratory disease problem presented a 
challenge, and it was recognized that observance of the principles of pre¬ 
ventive medicine had failed to keep respiratory infection rates within 
reasonable limits. Some form of protection was essential to continue the 
functioning of this Naval activity as an effective wartime military organi¬ 
zation. The situation became urgent. 

8 


All approved control measures against communicable disease were ob¬ 
served in so far as possible with facilities available at this station. The 
initial physical examination of incoming recruits was as thorough and 
searching in every detail as was consistent with the speed necessary to 
finish each day’s volume. A strict segregation by company was mam- 


CHART I 


SCARLET FEVER 
RATES IN FIVE NAVAL ^ 
TRAINING STATIONS 
1943*1944 


6MAT LAKES 
SAN D1E60 
NORFOLK 
SAMPSON 












The daily sick list approached 8 percent of the combined personnel of 
the station and a large percentage of the ill had severe hemolytic strepto¬ 
coccal infections; furthermore, about 200,000 men were leaving this station 
annually for other assignments or their homes, and about 30 percent of 
them were carrying in their throats highly communicable pathogens and 
virulent strains of hemolytic streptococcus. It was conceivable that mil¬ 
lions of streptococcal infections might be disseminated throughout the 
world. 

With a pandemic in the making, a program for the control of strepto¬ 
coccal infections by mass prophylaxis with sulfadiazine was initiated on 5 
December 1943. This is a report of various aspects of the Streptococcal 
Program at Farragut Naval Training Center between December 1943 
and April 1944. 

History and Methods of Study 

Mass sulfadiazine prophylaxis was first instituted in two camps of 
approximately 5,000 men each : Camp Bennion (C) and Camp Hill (D), 
Sulfadiazine, 1 gm., was administered daily to each recruit. Camps 
Waldron (A) and Ward (B) were used as controls. They were equal 
in size, identical in physical structure, and their personnel were drawn 
from the same population of incoming recruits as that of Bennion and Hill. 
Each of the four camps admitted companies of approximately 120 men 
from the Receiving Unit. These companies were sent in rotation to 
Camps Waldron (A), Ward (B), Bennion (C), and Hill (D). All re¬ 
cruits in these camps underwent identical training. At first, the program 
of mass prophylaxis was designed to permit carefully controlled observa¬ 
tions. From 5 December 1943 until 7 February 1944 each recruit at 
Camps Bennion (C) and Hill (D) was maintained on 1 gm. of sulfadia¬ 
zine daily; whereas recruits at Waldron (A) and Ward (B) received no 
chemoprophylaxis. Careful clinical and bacteriologic studies were made 
to determine the effect of the program on respiratory tract infections. 

On 17 January 1944 Camp Peterson (E), the Service School group 
which had had previous recruit training, either at this or some other sta¬ 
tion, was divided into two groups: Those living in the odd-numbered 
barracks received 0.5 gm. of sulfadiazine daily and those in even-numbered 
barracks received none. On 17 January 1944 Camp Scott (F), which 
was composed largely of special assignment recruits, was similarly divided 
into two groups: One received sulfadiazine, 0.5 gm. daily; the other 
group received no prophylaxis. These two camps were treated in this 
manner for 4 weeks when the entire complement of both camps was placed 
on a program of sulfadiazine prophylaxis. 

On 13 February Camps Waldron (A) and Ward (B), which had 
served as untreated controls, were each divided into two groups: In each 
camp the men in odd-numbered companies were given 0.5 gm. of sulfadia- 

9 


zine daily and those in even-numbered companies, 1 gm. daily. Clinical 
and bacteriologic data were collected in these four camps (A, B, E, and 
F) to determine the effectiveness of 0.5 gm. of sulfadiazine administered 
daily. 

On 13 February, all men in the Out-Going Unit of the station (average 
4,000 to 6,000) were given 1 gm. of sulfadiazine daily. Because of the 
tremendous variation in barracking, messing, and length of time on sta¬ 
tion, no attempt was made to use this group for controlled study. The 
duration of their stay in the Unit varied considerably and was frequently 
more than a month. 

On 6 March a daily prophylaxis of 1 gm. was instituted among the 
station personnel (about 6,000 men). At the same time prophylaxis was 
made available to officers and civilian employees throughout the station. 

In addition to records maintained regarding respiratory morbidity rates 
in all the treated and control groups, as many as possible of the ill in each 
group were seen by medical officers of the Epidemiology Unit. Throat 
cultures were obtained from an appropriate sample of recruits with re¬ 
spiratory infections. Positive cultures were graded from 1 to 4-plus, 
depending on the heaviness of growth of hemolytic streptococcus. Most 
of the positive cultures were sent to the National Naval Medical Center 
for grouping and typing by the Lancefield precipitin method. The re¬ 
sults of these examinations were mailed to this station. 

Clinical Re^ts 

Observations at Farragut .—Mass sulfadiazine prophylaxis at Farragut 
Training Center was highly successful. This was evident in the first 2 
weeks of the controlled study. Admissions for all bacterial infections of 
the respiratory tract in the two camps receiving prophylaxis dropped 
precipitously during the first week. Admissions for rheumatic fever 
dropped strikingly in the second week of prophylaxis. Virus infections 
were apparently not affected. The data collected prior to and during the 
first 2 weeks of prophylaxis are presented in table 2. 

Successive extensions of the program provided more information. The 
number of men reporting to sickbay with mild respiratory symptoms which 
did not require admission progressively decreased. Not only was the 
total amount of disease markedly lowered in the groups receiving prophy¬ 
laxis but also the relative importance of the bacterial infections was strik¬ 
ingly reduced in these groups. This is shown in chart 2. The effect of 
several extensions of sulfadiazine prophylaxis on the scarlet fever rate in 
January and February is also shown in chart 1. 

The extension of the program to all enlisted personnel about the first 
of March eliminated the untreated groups. As a result, controlled ob¬ 
servations were no longer possible. We therefore compared the trends 
during the spring months with trends indicated in Public Health Reports. 


10 


Table 2. —Respiratory diseases in four camps prior to and during first 2 weeks of 

sulfadiazine prophylaxis in Camps C and D 



11 


* Week ending. 

‘C.” is Control Group, about 10,000 men. “P.” is Group of about 10,000 men who received daily prophylaxis beginning 5 December 1943. 

























































































DISTRIBUTION, RESPIRATORY ILLNESS IN TREATED AND IN 
UNTREATED AREAS, ENTIRE STATION, N0V.28-MAR. 26 

( AREAS REPRESENT RELATIVE AMOUNT OF ILLNESS ) 


CHART 2 




■u* 


a 




w 


Ui 

u/ 


tA 


< ' 

• « 

m 

% ■ 

♦ o 


. w 

XiS 

Z 

•f 

A. 


! 


• 

•vu 





«u 

-4A 


3 ' 

< ■ 



Ui 



:» 


. -« . 


* 

, 2 

w. 

. 2 • 


cc 

s s 
> 
w 
u. 


S V5 


i/) 

< 

ui 

< 


■ O* 

U4 

, |»i^... , 

■ 

i-M 

QC . 
1*^ ■ \ 


12 


UKTREATED AREAS 






































SCARLET FEVER CASE RATES IN VARIOUS LOCALITIES 
(logarithmic curves) 


FARRAGUT 


ENTIRE HAVt 


MOUNTAIN STATES 


ENTIRE NATION 


ocm «W(> a io 27 otc. 


The influences of the extension of prophylaxis on the incidence of 
various respiratory diseases prevalent at Farragut were determined in the 
following way: The illness rate for the week preceding the use of sulfa¬ 
diazine on the station was taken as the base and given the value of 100 
percent. At this time the number of men not receiving sulfadiazine was 
100 percent. As the number of men receiving the drug increased, the 
value percent of men not taking sulfadiazine decreased until 6 March when 
all hands were ordered to take prophylaxis and the percentage fell theo¬ 
retically to zero. The associated decrease in illness of the more important 
disease is shown in chart 4. It is seen in this chart that, although most 
diseases declined as the number of men receiving sulfadiazine decreased, 
this was not true for pneumonia and otitis media. Subsequent bacterio- 
logic observations indicated that the type of pneumonia did change, how¬ 
ever, from one that was was predominantly streptococcal in origin to one 
that was predominantly pneumococcal. 


These observations are presented in chart 3. It is seen in this chart that 
the scarlet fever rate fell during the spring months at Farragut Naval 
1 raining Center, which was known to be heavily seeded with highly 
communicable scarlatinal strains of hemolytic streptococcus and to be re¬ 
ceiving a large number of susceptible recruits daily. At the same time 
it rose in the Mountain States and throughout the United States. 


H 15 ■ tt M.l .6 •• IS * 22 29 ' fSB-S (i 19 


13 






























The number of meningococcal and gonococcal infections was so small 
on this station that no conclusions can be drawn concerning the effective¬ 
ness of sulfadiazine prophylaxis. It is of interest, nevertheless, that in 
this large, overcrowded training center, meningococcus remained inactive 
throughout the course of this prophylactic program. 


CHART 4 


•EFFtCT OF SUIPHADIA2INF PROORAM ON IlLHESS RATES OF DISEASE* 

PERCENT OF POPULATION NOT ON SUIPHA0IA2IHE PROPHYLAXIS TO PERCENT » ILLNESS* 
•ILLNE^ RATE OF WEEK BEFORE PROPHYLAXIS STARTED 
(WEEK ENDING NOVEMBER 28j TAKEN AS'lOO PERCENT • 




xU 

OTITIC MtOlA 

TOtAL «€SI>lBATOfty 

CATARSHAl A£V£R 



PERCENT OF STATION NOT TAKING 
SULPHA0IA2INE PROPHYLAXIS 


DUPI PNCUMOHIA F8QM HOSHTAl ADMISSIONS ' 
PHEUMOAIA f»0M STATIOA ^ fORM 


Ejfect of Sulfadiazine Prophylaxis on Transmission of Streptococcal 
Infections to Other Eiwironments. —One concern to medical officers at 
Farragut was the transmission of highly pathogenic strains of hemolytic 
streptococcus to other Naval activities and to the civilian population. All 
recruits received 2 weeks’ leave following “boot” training, and each week 
large numbers of men in the Out-Going Unit were detached to other 
stations. It was disturbing that a large number of men who appeared in 
good health on departure from Farragut became ill with streptococcal 
diseases at home, en route, or shortly after arrival at another Naval ac¬ 
tivity. Sulfadiazine prophylaxis was therefore extended to the Out- 


14 



















CHART 5 



IN 3D 









Ou 

=> 

CD 

Oe: 

O 


CD 

lOJt 






cc 




cx. 

DD 

CD 

OC 

CD 

CD 

iJUi 

s 


oc 

I— 
Ds: 

«mD 






IS 





























EFFECT OF SULFAOtAZINE IN PREVENTING IMPLANTATION OF 
HEMOLYTIC STREPTOCOCCUS IN THE THROAT FLORA OF RECRUITS 
CONTROL COMPANY ^ ^ TREATED COMPANY 


CHART 6 



S3SV3 io mmid 


16 






Going Unit, and several investigations were made to determine whether 
the sulfadiazine program modified this epidemic process: 

1. The illness rate of men on leave who had taken prophylaxis was 
compared with the rate of illness among men from untreated groups. 
Favorable effects of sulfadiazine prophylaxis were observed. This is 
illustrated in chart 5. 

2. The incidence of men carrying hemolytic streptococcus in their throat 
flora at the end of recruit training was determined. It was found to be 
higher in the untreated companies than in treated companies. This is 
shown in chart 6. 

3. Letters of inquiry were sent to other Naval activities. The re¬ 
sponse to these requests for information indicated that less infection than 
had been observed previously occurred among Farragut transfers after 
all men in the Out-Going Unit had been placed on sulfadiazine prophy¬ 
laxis. 

Evaluation of 0.5 Gm. of Sulfadiazine as a Prophylactic Dose .—^The 
importance of determining the minimal effective daily prophylactic dose 
of sulfadiazine is obvious. Initial studies in Camps Peterson (E) and 
Scott (F) showed that 0.5 gm. was effective in controlling streptococcal 
illness. A comparison was then made between recruits receiving 1 gm. 
and those receiving 0.5 gm. of sulfadiazine prophylactically. On 6 Feb¬ 
ruary the odd-numbered companies in previously untreated camps, Wal¬ 
dron (A) and Ward (B), were given 0.5 gm. of sulfadiazine daily and 
the even companies were given 1 gm. daily. This was continued for a 
6 weeks’ period. 

Companies were assigned odd or even numbers alternately at the Re¬ 
ceiving Unit. A random distribution of such environmental influences 
as barracking, time in camp, messing, and other factors in the groups 
was assured. The diagnoses of patients admitted to the dispensaries and 
hospital were checked and the number of men appearing at sick call with 
respirator illness was recorded. Careful physical examinations of as 
many patients with respiratory illness as possible were made by medical 
officers of the Epidemiology Unit, and throat cultures taken at this time 
were examined for hemolytic streptococci. Data on the effectiveness of 
the two dosages are presented in table 3. 

Table 3, comprising the morbidity data obtained from the admission 
diagnoses in the two groups, shows that the differences in effectiveness 
of the two dosages are slight. In catarrhal fever, in total respiratory in¬ 
fections, and in total respiratory sick call there is a small but statistically 
significant difference in favor of 1 gm. of sulfadiazine over 0.5 gm.; how¬ 
ever, the incidence of diseases commonly considered to be streptococcal in 
origin, such as pharyngitis, tonsillitis and scarlet fever, was lowered as 
effectively by 0.5 gm. as by 1 gm. of sulfadiazine. If all the diseases 
whose causative agents have been found susceptible to sulfadiazine pro¬ 
phylaxis are grouped together (total of respiratory infections in table 3), 

17 



* 

r 

K. 



18 


♦ Average weekly population. 





















































a difference in morbidity rate of only 1.10 per thousand men per week is 
found in favor of 1 gm. over 0.5 gm. Between 20 and 30 times out of a 
hundred, such a difference could arise by chance. In a smaller group of 
patients given more detailed diagnostic examination by the epidemiologic 
medical officers, no significant difference in the effectiveness of the two 
drug dosages could be shown. Furthermore, in these patients cultures of 
the throat showed no significant differences; the percentages of culture 
negative and positive for hemolytic streptococcus were similar in the 
two groups. 

In summary, 0.5 gm. appears to be approximately as effective as 1 gm. 
in preventing streptococcal infections. The rate of untoward reactions 
is lower with the smaller dose. The simplicity of administration and the 
saving in cost of the drug favor the use of 0.5 gm. daily. It is obvious 
that in any future prophylactic use of sulfadiazine 0.5 gm. of this drug 
daily should be tested on a large scale. 

Man-Days Saved 

The first 3 months of the controlled program saved more than 100,000 
man-days of enlisted personnel and concomitantly relieved heavy demands 
on medical personnel. The extension of sulfadiazine prophylaxis can be 
expected to create a greater saving. 

The direct saving in man-days was estimated on the assumption that 
the difference in illness between control and treated groups represented 
the amount of illness prevented. Figures for man-days lost for each 
type of illness were obtained from the Bureau of Medicine and Surgery. 
The number of admissions saved was calculated separately for each type 
of Naval personnel for each disease. This was done by comparing the 
admission rates in control and treated areas where controlled observations 
were made or, in the case of the Out-Going Unit and of the Ship’s Com¬ 
pany, by comparing the admission rates before and after the administra¬ 
tion of sulfadiazine. Man-days saved were then the product of admissions 
prevented in each disease and the average number of sick days for each 
type of illness. Figures were adjusted to the basis of 1,000 men taking 
prophylaxis for 1 week. From this, figures on man-days saved in actual 
administration could be simply calculated, because it was known how 
many men had been taking prophylaxis and for how long a time. 

The effectiveness of sulfadiazine prophylaxis in saving man-days is. 
determined by several factors: 

1. The greater the amount of respiratory disease occurring in a group, 
the greater will be the saving in man-days as a result of sulfadiazine pro¬ 
phylaxis. For example: More illness can be prevented among recruits 
with a high rate of infections than in seasoned men of Ship’s Company 
with a low rate of infections. 


19 


2. The greater the bacteri®static effect of the drug, the greater the 
savings will be as a result of prophylaxis. For example: Sulfadiazine 
is more effective in preventing scarlet fever or meningitis than pneumonia. 

3. The more time required for recovery from a particular disease, the 
more man-days will be saved. For example: The man-days lost for one 
admission with rheumatic fever is equivalent to about 16 admissions for 
acute tonsillitis. 

4. The greater the number of man-days of sulfadiazine prophylaxis, 
the larger will be the number of man-days saved. 

The relation of some of these factors to the accumulated man-days 
saved is shown in tables 4 and 5. It is seen in these tables that the saving 
in man-days at Farragut occurred among recruits and that this was due 
especially to the prevention of scarlet fever and rheumatic fever. Such 
a preventive measure also carries with it a tremendous saving in salaries 
and pensions. 


Table 4. — Saving in man-days hy prevention of respiratory illnesses with 
sulfadiazine prophylaxis, December 19^3 to April 194^4^ 


Groups of personnel 

Saving per 
1000/week 

Man-weeks 

of 

prophylaxis 

Man-days 
saved 
by groups 
receiving 
prophylaxis 

Recruits. 

Special AsaipTiTnent, 

343 

248 

56 

32 

33 

248,879 

41,905 

47,199 

33,787 

17,798 

85,372 

10,391 

2,643 

1,082 

587 

Service Schools 

Out-Going Unit... . 

Ship’s Company. 

Total ..... 

*315 

389,568 

100,075 


♦Weighted. 

Table 5. — Saving in man-days per 1000 of recruits for 10 important 
respiratory diseases 

Diseases 

Regular 

recruits 

Limited 

duty 

recruits 

Percent of total population. 

49.1 
148.1 

94.5 
41 3 

14.1 
15.3 

9.2 

6.3 

6.3 
5.8 

2.4 

12.3 

29.6 
62.9 
78.1 

15.7 

13.4 
2.8 

32.4 
1.6 
4.6 
7.1 

Scarlet fever___ 

Rheumatic fever... 

Catarrhal fever .. 

Tonsillitis. 

Otitis media. 

Bronchitis, larvneitis. etc. 

(All types) Pneumonia. 

Pharyneitis—. 

Sinusitis.. 

Meningococcus meningitis. 



20 








































Bacteriologk Studies 

Effect of Sulfadiazine Prophylaxis on Prevalence of Hemolytic Strepto¬ 
coccus in Throat Flora. —It is frequently difficult to make an etiologic 
diagnosis of a respiratory disease on clinical examination. This difficulty 
is partly overcome by an accurate appraisal of the respiratory pathogens 
present in the throat flora. We have made careful cultural studies of the 
throat flora of patients with respiratory infections, primarily as an aid to 
diagnosis but also to determine the effectiveness of sulfadiazine prophy¬ 
laxis on the activity of hemolytic streptococcus among Naval personnel. 

It is well recognized that persons with streptococcal respiratory disease 
have a higher proportion of hemolytic streptococcus in their throat flora 
than those who carry this organism coincidentally, either in the course of 
a non-streptococcal disease or during good health. We have therefore 
recorded the incidence of positive throat cultures in the various groups of 
men and also have determined the proportion of hemolytic streptococci in 
positive cultures. For convenience we have used the following scale: 
Predominant is called 4 plus; heavy growth, 3 plus; moderate number, 
2 plus; few hemolytic streptococci, 1 plus. Comparisons were made be¬ 
tween the throat culture findings in the groups receiving prophylaxis and 
in the untreated controls. 

Initial results showed that (1) the absolute number of patients with 
throat cultures containing hemolytic streptococci was less in the treated 
groups; (2) the proportion of all respiratory diseases with positive cul¬ 
tures was less in the treated groups; (3) cultures with a heavy growth 
of hemolytic streptococci, 3 plus or 4 plus cultures, were strikingly less 
common in the treated groups. Further studies were then made to deter¬ 
mine the influence of sulfadiazine prophylaxis on streptococcal activity. 


Table 6. —Relation of the presence and proportion of hemolytic streptococcus 
to sulfadiazine prophylaxis in the throat flora of patients with 
respiratory diseases 


Throat culture findings 

Regular 

prophylaxis 

Irregular 

prophylaxis 

No prophylaxis 

Num¬ 

ber 

Per¬ 

cent 

Num¬ 

ber 

Per¬ 

cent 

Num¬ 

ber 

Per¬ 

cent 

Negative.... 

261 

76.1 

90 

66.7 

226 

49.8 

One and Two Plus. 

40 

11.7 

18 

13.3 

89 

19.6 

Three and Four Plus. 

42 

12.2 

27 

20.0 

139 

30.6 

Total._. 

343 

100.0 

135 

100.0 

454 

100.0 


Men from whom cultures were to be taken were divided into three 
groups: (1) those who took prophylaxis regularly; (2) those who took 
prophylaxis irregularly, and (2) those who took no prophylaxis. Studies 
of throat cultures in these three groups showed that the more regularly 


21 
















prophylaxis was taken, the more negative cultures there were and the 
fewer strongly positive cultures were obtained. These data are presented 
in table 6. It was also found that in patients with the same admission 
diagnosis, the absolute and relative number of strongly positive cultures 
was less in the treated than in the untreated group. This was particu¬ 
larly striking in patients with the diagnosis of catarrhal fever (chart 7). 
In our opinion, there was either more streptococcal disease in the con¬ 
trol group or less in the group receiving prophylaxis than is actually 


CHART 7 


c 


15 - 

14 - 

13 - 

12 - 


AMOUNT OF ILLNESS AND RESULTS OF THROAT 
CULTURES FOR HEMOLYTIC STREPTOCOCCI 
DISEASE IN TREATED AND UNTREATED GROUPS 
FOR ENTIRE STATION DURING PERIOD OF 
CONTROLLED OBSERVATION 
arranged in order of difference in admission rates 


11 - 


V: 

UJ 

Uj 

tt 

Uj 

Q. 

Q 

V) 

o 

3: 


£ 

Q. 


Uj 

k. 

It 


IQ¬ 

S' 


D 



NEGATIVE CULTURE 
I^ANO 2* CULTURES 



CATARRHAL SCARLET TONSILLITIS RHEUMATIC 

FEVER FEVER FEVER 


OTITIS BRONCHITIS PHARTNOITIS SINUSITIS 

MEDIA LARYNGITIS 

ETC. 


22 


















indicated by morbidity rates of frank or presumptive streptococcal disease. 

Serologic Types of Hemolytic Streptococci Prevalent at Farragut .—The 
outstanding clinical characteristics of streptococcal activity at Farragut 
were: (1) the high incidence of scarlet fever; (2) the high incidence 


Table 7. —Incidence of different types of hemolytic streptococci recovered 
from throat flora of patients ivith respiratory tract infections at Farragut, 
January through March 19AU 


Group A 

Number 

Percent 

Tvpe1_ 

60 

14 80 


0 

0.00 

S 

21 

5.20 


1 

0.25 

B 

3 

0.74 

6. 

5 

1.23 


1 

0.25 

9 

2 

0.49 


0 

0.00 

12. -... 

3 

0.74 


3 

0.74 

17. 

156 

38.60 

18 

6 

1.48 

19 

89 

22.00 

24___ 

8 

1.98 

26_ _ 

0 

0.00 

28 

2 

0.49 

29 

0 

0.00 

30 

1 

0.25 


0 

0.00 

33 


0.25 

36 

7 

1.73 

39 

0 

0.00 

41..-. 

0 

0.00 

43.. 

p 

0.00 

44 . 

1 

0.25 

46.... . 

0 

0.00 

?.. 

34 

8.42 

Total—Group A.. 

404 

91.60 

Orniip A* ... . .. _ 

37 

8.40 

OTd-minpd . 

441 






* These specimens include Beta hemolytic streptococcus not of Group A, cultures not Beta hemolytic 
streptococcus and cultures not suitable for examination on arrival. 


and severity of rheumatic attacks following streptococcal infections; (3) 
the occurrence of a large number of cases of primary streptococcal pneu¬ 
monia which frequently gave rise to suppurative processes. The rapidity 
with which these infections were contracted by recruits and the severity 
of the clinical characteristics indicated that the Farragut strains of hemo¬ 
lytic streptococcus were both highly communicable and unusually viru¬ 
lent. It was, therefore, of interest to determine whether one, several, or 
m.any strains were operative at this station. Serologic identification of 
the causative agents proved helpful in determining this point. 


23 














































24 









































Altogether 441 cultures from patients with respiratory diseases were 
shipped during the winter months to the Bethesda laboratory for typing. 
The results are presented in table 7. It is seen in this table that many 
serologic types were recovered from different respiratory diseases, but that 
type 17 was the most common respiratory pathogen in the throats of these 
patients. Table 8 shows further that type 17, in relation to all other 
serologic types, appeared with frequency in scarlet fever, rheumatic fever, 
and empyema. Types 3 and 19 also caused scarlet fever frequently and 
type 1 gave rise to empyema. It appeared, nevertheless, that the ex¬ 
cessively high morbidity rates for scarlet fever, rheumatic fever, and strep¬ 
tococcal empyema at Farragut were associated with the activity of group 
A, type 17, hemolytic streptococcus. 

Untoward Sulfonamide Reactions 

Difficulties anticipated at the onset of this program included: (1) high 

incidence of sulfadiazine sensitization phenomena; (2) severe drug reac¬ 
tions terminating fatally; (3) sensitizing a large number of personnel to 
sulfonamide. Some of these anticipated untoward effects materialized. 

Mild Sensitisation Phenomena .—During the first 4 months of this sul¬ 
fadiazine program. Naval personnel at this training center had approxi¬ 
mately 350,000 man-exposure weeks to sulfadiazine prophylaxis. It is 
estimated that approximately 80,000 men have already received sulfadia¬ 
zine prophylaxis. Recruits in the Service Schools have received prophy¬ 
laxis for as long as 16 weeks. The average period in which each man 
received sulfadiazine was about 4^2 weeks. 

Mild evanescent dermal reactions, exhibited as a scarlatiniform or mor¬ 
billiform eruption, were relatively common. In the examination of 
16,303 recruits, 0.47 percent of those taking 0.5 gm. daily and 0.75 per¬ 
cent of those taking 1 gm. daily were found to have rashes on the day of 
examination. The clinical characteristics of all types of reactions are 
reported by other Naval Epidemiology Units in the following pages. A 
brief account of the severe reactions is given in this report. 

Severe Drug Reactions .—Severe reactions were rare; three types were 
observed: (1) exfoliative dermatitis; (2) bullous skin lesions; (3) 
granulocytopenia. During the 4-month period covered by this report 
there were 39 severe reactions. These included untoward effects from 
both therapeutic and prophylactic doses of sulfadiazine. The association 
of three types of reactions with chemoprophylaxis and chemotherapy is 
shown in table 9. 

There were six fatalities from sulfonamides during this program; all 
resulted from granulocytopenia. Two of these occurred among men on 
leave, and four in Farragut Naval Hospital. Of the four in Farragut, 
one man had received no prophylaxis; the other had aplastic anemia. 
The one who had received no prophylaxis died following sulfonamide 

25 


Table 9.— Association of severe sulfonamide reactions 
with prophylaxis or therapy 


Disease 

Total 

number 

Number 

from 

prophylaxis 

alone 

Number 

from 

therapy 

alone 

Number 
from both 
therapy and 
prophylaxis 

Exfoliative dermatitis .. 

1 

1 

0 

0 

Bullous skin and mucous membrane lesions. 

22 

8 

0 

14 

Granulocytopenia. 

16 

3 

2 

11 


therapy. Two of the four had had sulfadiazine prophylaxis and had been 
given sulfadiazine therapy. One had received prophylaxis and a trans¬ 
fusion with blood containing sulfadiazine. The results indicate that 
therapeutic doses of sulfonamide aggravated a severe disease process 
initiated by prophylaxis. They also indicate that if the therapeutic use 
of sulfonamides is foregone among personnel receiving prophylaxis until 
the diagnosis is established, fatalities can be prevented. 

Observations on the Danger of Sensitising Naval Personnel .—^We have 
observed that relatively few who have contracted infections while receiv¬ 
ing prophylactic doses of sulfadiazine are unable to take therapeutic doses 
of the drug. For example, 252 of the patients with pneumococcus pneu¬ 
monia who had on previous occasions received sulfadiazine prophylaxis 
were treated exclusively and effectively by sulfadiazine in most instances. 
Furthermore, many who showed an initial dermal reaction to the sulfa¬ 
diazine were subsequently replaced on the program without ill effects. 
All these men were observed closely when sulfadiazine prophylaxis was 
resumed after an interval of 2 weeks. 

Sulfadiazine was given for as long as 2 months in the Out-Going Unit 
to all recruits who returned from their 2 weeks’ leave. These recruits 
had received the drug during their “boot” training, had discontinued it 
for 2 weeks, and then resumed prophylaxis. This incidence of drug re¬ 
actions was not increased. 

In summary, a small percentage exhibited sensitivity to prophylactic 
or therapeutic doses of sulfadiazine. The prophylactic program did not 
appear to sensitize large numbers of men. 

Observations Regarding Possible Development of Sulfonamide 
Resistance by Respiratory Pathogens 

With the extension of sulfadiazine prophylaxis to the entire station, 
attention was directed to determining whether the prevalent strains of 
hemolytic streptococcus might develop resistance to sulfadiazine. If drug 
resistance did develop, it could be expected to manifest itself in one or 
more of the following ways: 

26 











1. During the continuation of the prophylactic program the morbidity 
rate of streptococcal diseases would increase as the resistant organisms 
gained in prevalence. 

2. Certain types of group A organisms might develop more resistance 
than others and would accordingly appear with increasing frequency in 
throat cultures of patients with upper respiratory tract diseases. 

3. Bacterial infections, previously amenable to sulfonamide therapy, 
would become increasingly more difficult to treat with this chemothera¬ 
peutic agent. 

4. Hemolytic streptococci or other organisms isolated from treated 
patients would show evidence of sulfonamide resistance by laboratory 
tests. 

Evidence that drug resistance did not develop during this 4-month 
period is presented in the following paragraphs: 

Effect of Continued Sulfadiazine Prophylaxis on Rate of Illness .—In 
February, Camps Bennion (C) and Hill (D), which had been on the pro¬ 
gram longest, experienced an increase in the respiratory sick call rate and 
in total respiratory infections. This rise was associated in Camp Hill 
(D) with an increase in streptococcal infections (scarlet fever, tonsillitis 
and pharyngitis) but this was not apparent in Camp Bennion (C). Be¬ 
cause the rising morbidity rate at Hill (D) might indicate a decrease in 
the effectiveness of the program, this possibility was investigated during 
the first 2 weeks in April. All patients with respiratory illness were seen 
by the medical officers of the Epidemiology Unit. Throat cultures were 
taken and sulfadiazine blood level determinations were made for patients 
believed to have streptococcal disease. 

The observations indicated that there was an increase in the streptococ¬ 
cal diseases over the first months of the program. The number of posi¬ 
tive cultures, and particularly 3 and 4 plus cultures, was higher in April 
than in December and January. This is shown in table 10. The mean 
blood level of 26 patients with positive cultures was 1.38 mg. percent; 
6 of these patients had values above 2 mg. percent. 

One might expect that the rising rates of upper respiratory tract dis¬ 
eases would be higher in the camps on the drug program for the longest 
period and less marked in the camps most recently placed on prophylaxis. 
As the morbidity statistics for April were recorded week by week, it be¬ 
came apparent that the rise in streptococcal morbidity was occurring in 
all recruit areas and was not related to the time that they had been on 
prophylaxis. This is shown in chart 8. Further confirmation was ob¬ 
tained by sample throat cultures taken from patients with respiratory 
diseases in the different areas. Although not strictly comparable, the 
results indicated that Camp Hill (D) had no higher rate than many other 
areas and that Camp Bennion (C) had the lowest rate of all recruit 
groups. 


27 


Table 10 .—Prevalence of hemolytic streptococci in throat cultures taken from 
a random sample of respiratory disease in early winter and spring 


• 

Throat cxiltxire findings 

January and February 

April 

Number 

Percent 

Number 

Percent 


148 

81.4 

100 

60.0 

Onp and t.wn plus____ 

11 

6.0 

30 

15.0 

Three and four plus.. .... 

23 

12.6 

70 

35.0 

Total . . 

182 

100.0 

200 

100.0 






CHART 8 



28 
















































































































In summary, a rise in streptococcal disease rate did occur; however, 
it was independent of the length of time in which the sulfadiazine pro¬ 
gram had been in effect. We are of the opinion that this rise was a 
reflection of the general increase in streptococcal infection usually seen 
in civilian and untreated military populations during March and April. 
The collected observations showed that there was no relation between 
prolonged chemoprophylaxis and diminution in effectiveness. 

Prevalence of Different Types of Hemolytic Streptococcus During the 
Program. —If sulfonamide resistance were developing in strains of hem¬ 
olytic streptococcus, one might anticipate that among those who became 
infected while receiving prophylaxis there would be an increase in the 
incidence of certain types because nonresistant types would be less likely 
to cause illness in these men. The phenomenon of natural selection would 
be expected to operate, and a resistant strain would become predominant 
as the program was extended. Furthermore, if a comparison were made 
between the types recovered from those on prophylaxis and from those 
in control groups, the more resistant types would appear with greater 
frequency in the former group. Neither of these possibilities materialized. 
As is shown in table 11, there was no significant change in the types 
of streptococci present in respiratory illness in the last 3 months of this 
program; moreover, there was no essential difference in the distribution 
of types of hemolytic streptococci recovered from patients with respira¬ 
tory infections irrespective of whether or not they had received prophy¬ 
laxis prior to the onset of illness. 

In summary, observations madea during 3 months of prophylaxis indi¬ 
cated that no strains of hemolytic streptococcus developed resistance to 
sulfadiazine. 

Resistance of Hemolytic Streptococcus to Therapeutic Doses of Sulfa- 
diasine. —Patients with streptococcal infections showed a satisfactory clin¬ 
ical response to sulfonamide therapy throughout this program. Further¬ 
more, a large majority of patients who developed pneumonia despite pro¬ 
phylaxis were treated with sulfadiazine. Approximately 90 percent of 
these patients responded satisfactorily to sulfadiazine therapy; penicillin 
was used in the remaining cases. The clinical results of sulfadiazine 
therapy compared favorably with those of other Naval hospitals. The 
development of drug fastness was not observed. 

Laboratory Investigation of Sulfonamide Resistant Strains of Hemo¬ 
lytic Streptococci. —Strains of hemolytic streptococci obtained in cases 
of streptococcal infections contracted during prophylaxis were isolated 
and sent to the National Naval Medical Center, for studies of sulfonamide 
fastness. Our laboratory also made attempts to show sulfonamide resist¬ 
ance in these organisms. Up to the present time there has been no evi¬ 
dence of drug resistance in group A hemolytic streptococcus at Farragut. 

29 


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30 

















































































In summary, no evidence from a clinical, epidemiologic or bacteriologic 
standpoint was obtained that hemolytic streptococci became resistant to 
sulfadiazine during 4 months of the prophylactic program. 

Comment 

Environmental conditions at Farragut Naval Training Center in 1942 
and 1943 were favorable to the initiation and perpetuation of epidemics 
of respiratory tract diseases. Shortly after the opening of this station 
an excessively high morbidity from streptococcal infections accompanied 
by high attack rate for rheumatic fever presented a serious problem. It 
was hoped that activity of hemolytic streptococcus would subside during 
the summer months of 1943; however, this did not occur. The sum¬ 
mer months were dry; daily dust storms, aggravated by the clearing 
of large areas for construction, were irritating to the respiratory tract; 
the rate of scarlet fever was maintained at plateau level. An outbreak 
of influenza (catarrhal fever) occurred in October with the onset of 
cooler weather; streptococcal activity, already at a high level, increased 
within a few weeks. By November the morbidity rate from scarlet fever 
and rheumatic fever was disturbingly high. This was soon followed by 
the appearance of primary streptococcal pneumonia and empyema. The 
problem of preventing the dissemination of bacterial respiratory pathogens 
was complicated by a marked increase in the incidence of measles early 
in the winter of 1944. All the factors essential for the initiation and 
perpetuation of a severe streptococcal epidemic, and perhaps even a pan¬ 
demic, appeared to be operative at this training center. It was urgent 
to check the dissemination of Streptococcus hemolyticus which had al¬ 
ready acquired extensive communicability and to prevent the transmission 
of these highly pathogenic strains to other environments. Sulfadiazine 
prophylaxis was selected to attain these objectives, and these objectives 
were achieved. 

Summary 

1. A prolonged epidemic of streptococcal diseases, characterized at 
first by large numbers of cases of scarlet fever and rheumatic fever, and 
later by the development of cases of primary streptococcal pneumonia 
occurred at the United States Naval Training Center, Farragut, Idaho, 
during 1943 and 1944. 

2. Sulfadiazine prophylaxis was instituted in December 1943. At first, 
a controlled study was made; later, all personnel on the station were given 
chemoprophylaxis, 1 gm. daily. 

3. Morbidity rates and bacteriologic studies of treated and untreated 
groups served as the basis for reaching the following conclusions: 

(a) The number of patients reporting to sick call with minor respir¬ 
atory symptoms but not requiring admission was markedly reduced. 


31 


(b) The admission rates for bacterial respiratory tract infections were 
significantly reduced in those recruits who received prophylactic doses 
of sulfadiazine. 

(c) The fall in the incidence of catarrhal fever, scarlet fever, tonsil¬ 
litis, pharyngitis, suppurative infections, and rheumatic fever was striking. 

(d) Primary streptococcal pneumonia was eliminated by sulfadiazine 
prophylaxis. 

(e) No case of meningococcus meningitis occurred in those taking 
sulfadiazine prophylaxis. 

(f) The incidence of virus infections, such as measles and mumps, was 
not aflPected by sulfadiazine prophylaxis. 

4. As the portion of the station receiving prophylaxis was increased, 
the morbidity rate for all respiratory diseases declined. 

5. Although the attack rate from pneumonia was less in treated than 
in control groups, the morbidity rate for pneumococcus pneumonia re¬ 
mained high even after the entire station was placed on a program of 
sulfadiazine prophylaxis. Clinical and laboratory observations indicate 
that strains of type 5 pneumococcus prevalent at Farragut were resistant 
to small concentrations of sulfadiazine. 

6. Less illness occurred among recruits on leave from the camps receiv¬ 
ing prophylaxis than from camps in which chemoprophylaxis had not 
been instituted. 

7. Administration of the drug to approximately 80,000 men in 3 months 
saved more than 100,000 man-days on this station. The saving of time 
was greater among new recruits and is attributed largely to the preven¬ 
tion of scarlet fever and rheumatic fever. 

8. Throat cultures obtained from patients with respiratory infections 
and examined for hemolytic streptococci were more frequently negative 
and showed less heavy growth in those patients receiving prophylaxis than 
in the control groups. 

9. Type 17 was the most prevalent and perhaps the most pathogenic 
strain of hemolytic streptococcus at Farragut. Type 19 and type 1 were 
the next most common. 

10. Type 17 was the respiratory pathogen most frequently associated 
with the development of scarlet fever, rheumatic fever, and streptococcal 
empyema. 

11. In preventing most streptococcal infections, 0.5 gm. of sulfadiazine 
was approximately as effective as 1 gm. 

12. The incidence of dermal reactions was 0.75 percent on 1 gm. dosage, 
and 0.47 percent on 0.5 gm. dosage. 

13. The 3 types of severe sulfadiazine reactions encountered were: 
(a) exfoliative dermatitis; (b) bullous skin and mucous membrane 
lesions; (c) granulocytopenia. These reactions were aggravated by the 
administration of therapeutic doses of the sulfadiazine to men who had 
received prophylaxis. 

32 


14. Six deaths occurred; all were associated with granulocytopenia. 
With possibly one exception, all are ascribed to therapeutic doses of sul¬ 
fadiazine. 

15. No evidence was obtained from this large number receiving sulfa¬ 
diazine that prophylaxis sensitizes, or that it militates against the thera¬ 
peutic application of sulfonamides. 

16. There was no evidence that hemolytic streptococcus became sul¬ 
fonamide-fast during this prophylactic program.^ 

17. Mass sulfadiazine prophylaxis is an effective method for control¬ 
ling bacterial respiratory tract infections. 

1 During the summer months (since this report went to press) clinical and bacteriologic 
findings have indicated that strains of Types 19 and 17 recovered at this naval activity are 
resistant to prophylactic doses of sulfadiazine. 


I 





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'>^>S-jLA Tr- 







Report 3 


A Study of the Sulfadiazine Streptococcus Prophylaxis 
Program at the Great Lakes Training Center 

Prom the Epidemiology Unit* 


he high incidence of respiratory diseases among personnel of military 
installations led to the study of prophylactic use of sulfadiazine in reducing 
the respiratory diseases of proved streptococcal origin and other respira¬ 
tory diseases. This study was conducted at the United States Naval 
Training Center, Great Lakes, Illinois, during the period extending from 
1 December 1943 to 15 April 1944. 

General Description of Naval Station 

Great Lakes Naval Training Center is in effect a series of self-sustain¬ 
ing camps, each having its own dispensary and sickbay, mess hall, galley, 
drill hall, drill field, and recreation facilities. The camps are distributed 
as follows: 

1. Twelve camps are used for training new recruits: six are in the 
Green Bay area, three in the Downey area, and three are entirely for 
Negro training 

2. Three camps are used for the Service School, Out-Going Unit, and 
Marine barracks. For administrative purposes, men in the Service 
School are divided into Group I, Group II, and Group III. This group¬ 
ing was used in selecting the men who were to be treated, and to be held 
as controls. 


* Participants: Lucius E. Eckles, Lieutenant Commander (MC) USNR; Ernest 
L. Woodman, Lieutenant (MC) USNR; Rocco G. Lapenta, Lieutenant (MC) 
USNR; James H. Huyck, Lieutenant (MC) USNR; Christian V. Cimmino, 
Lieutenant (MC) USNR; Harold E. Hoff, Ensign H-V (S) USNR. 

Technical Assistants: A. W. N. King, PhMlc, USNR; Glen E. Finley, PhMlc, 
USNR; Richard C. Hartsfield, PhMlc, USNR; Ramona E. Nieberding, PhMlc, 
USNR; Jo A. Robar, PhMlc, USNR; Martin G. Austin, PhM2c, USNR; Carlyle 
D. Hummel, PhM2c, USNR; Dorothea D. McCreedy, PhM2c, USNR; Thomas 
C. Kessler, PhM2c, USNR; Rosalie M. Erspamer, PhM2c, USNR. 


35 




3. One camp is used as a reception center. The recruits are exam¬ 
ined here and then assigned to recruit camps. 

4. One camp (Camp Mclntire or Mclntire Dispensary) is essentially 
the hospital, taking care of those patients whose condition is too serious 
to be cared for in the outlying camp dispensaries. Most patients with 
scarlet fever, mumps, and German measles are sent to Mclntire. All 
other patients with contagious diseases are sent to the nearby U. S. Naval 
Hospital, which comprises a separate command from that of the Training 
Center. 

5. All these various activities are closely knit together by the “Main 
Side” area which houses the administrative offices. 


Method 


The task of carrying out this study was given to the Epidemiologic 
Unit, consisting of five medical officers, two H-V(S) officers, and nine 
hospital corpsmen. Chart 9 shows the plan for distribution of sulfadia¬ 
zine prophylaxis among the several participants. 


CHART 9 



Beginning 1 December 1943, the recruits in the Green Bay area and 
the men in Service School, Group I, were given 1 gm. of sulfadiazine 
daily, and the recruits from Downey area and the men in Service School, 
Groups II and III, were held as controls. The Green Bay area was se¬ 
lected for the treated group because this area had a previous incidence of 
respiratory diseases consistently higher than the Downey area; Service 
School, Group I, was chosen arbitrarily. This plan among the recruits 
(Downey and Green Bay Areas) was not changed until 13 March 1944, 
when both areas were placed on a program of sulfadiazine prophylaxis. 
The Service School plant (Groups I, II, and III) was not changed until 
1 February 1944, when Groups II and III were given sulfadiazine and 

36 







































Group I was held as control. On 1 March 1944, all the Service School 
(Groups I, II, and III) were given sulfadiazine. 

On 13 March 1944, the program was extended, so that all the enlisted 
personnel attached to Great Lakes Naval Training Center received sul¬ 
fadiazine prophylactically. 

Insofar as possible, the men ingested the drug under direct supervision 
of company commanders. Service School instructors, and departmental 
representatives. The two tablets (0.5 gm. each) were taken together, at 
a regular time during the day compatible with the daily routine. 

A throat culture for beta hemolytic streptococci and a blood sulfadia¬ 
zine level were taken of all patients admitted for respiratory disease. 
Diagnoses of rheumatic fever, pneumonia, meningitis, and scarlet fever 
made on admission were confirmed by personal follow-up. Diagnoses 
of all other respiratory diseases were accepted. 

All men with a definite or suggested sulfonamide reaction were with¬ 
drawn from the program. Insofar as possible a medical officer of the 
epidemiology unit personally observed all eruptions and retested a large 
percentage. A throat culture and blood sulfadiazine level were taken of 
all reactors. 

All the beta hemolytic streptococci isolated from the sulfadiazine- 
treated and control patients were subcultured and sent to the laboratory 
at the National Naval Medical Center for grouping and typing. 

A sampling of leukocyte counts and urinalyses was taken to determine 
the prevalence of untoward effects of prophylactic sulfadiazine on the 
hematopoietic and urinary systems. 

The weekly and monthly incidences of the various respiratory diseases 
among the treated and untreated groups were calculated and graphed. 
An epidemiologic study of the streptococcus types was done. An evalua¬ 
tion of the frequency, severity, and modifying factors of sulfadiazine skin 
manifestations was made. 

The following diseases are referred to by the term ‘'upper respiratory 
infections”: scarlet fever; tonsillitis, acute; pharyngitis, acute; catarrhal 
fever, acute; laryngitis, acute; bronchitis, acute; tracheitis, acute; rhinitis, 
acute; Vincent’s infection; sinusitis, acute; otitis media, acute; mastoiditis, 
acute; tracheobronchitis. 

When “all respiratory infections” are mentioned, the following are in¬ 
cluded in addition to the listed diseases: primary atypical pneumonia; 
bronchopneumonia; lobar pneumonia; cerebrospinal fever (meningo¬ 
coccus). 

Effect of Prophylactic Sulfadiazine on Respiratory Diseases 

Daily Respiratory Complaints at Sick Calls .—Charts 10 and 11 show 
that immediately following the institution of sulfadiazine prophylaxis in 
the recruit camps and Service School the respiratory symptoms in the 

37 


treated groups fell precipitously; whereas the control groups varied ac¬ 
cording to seasonal incidence. The rates in the Service School before 
the program was begun unfortunately cannot be shown because the group¬ 
ings of the men reporting at sick call were not recorded prior to the 
institution of the program. It is not clear why the rates m the treated 
recruit camps gradually increase and approach the rates of the untreated 
camps; however, the rates in the treated recruit camps never reached the 
levels obtained before the program was begun. It should be pointed out 
that the increase in the rates of respiratory symptoms among the treated 
groups was not reflected in the admissions for respiratory disease. The 
precipitous fall in the rates of the controls in the recruit camps as shown 
in chart 10 was coincident with expansion of the program to include all 
enlisted personnel. 

Chart 11 shows the constant level of the respiratory symptoms among 
the treated men (Group I) of Service School as contrasted with the find¬ 
ings shown in chart 10. As soon as prophylaxis was discontinued the 
respiratory complaints increased. 

Total Admissions for Respiratory Diseases to Dispensaries and Hos¬ 
pital .—Charts 12 and 13 show the striking and sustained difference be¬ 
tween the rates of admissions for respiratory disease in the treated and 
control groups in both the recruit camps and the Service School. 

It is seen from chart 13 that the admission rates in Group I did not 
greatly increase during the month of February even though prophylaxis 
was discontinued during that month; possibly this resulted from reduction 
of bacterial flora during the previous period of sulfadiazine prophylaxis. 

Effect of Prophylactic Sulfadiazine on Diseases of Streptococcal Origin 

Charts 14 and 15 show the persistent effect of prophylactic sulfadiazine 
in reducing the incidence of scarlet fever, tonsillitis, and pharyngitis 
among the treated men in the recruit camps and the Service School. 

Effect of Prophylactic Sulfadiazine on Incidence of Catarrhal Fever 

Chart 16 shows a precipitous decrease in the incidence of catarrhal 
fever among the treated recruits. This behavior is not compatible with 
the accepted virus etiology of the group of upper respiratory diseases 
called '‘catarrhal fever” in Navy nomenclature. Several explanations 
might be offered, prominent among which is the one that many “catarrhal 
fevers” are in reality beta hemolytic streptococcus infections with consti¬ 
tutional rather than local symptoms predominating. The evidence for 
this conception is the striking similarity between the figures depicting 
the behavior of streptococcus infections and catarrhal fever in the recruit 
camps. Further, it has been observed that-2.4 percent of 781 men with 
catarrhal fever taking prophylactic sulfadiazine had throat cultures Dosi- 

38 


CHART 10 





39 


















































































































CHART II 



40 



















































CHART 12 



41 











































































CHART 13 



42 














































CHART 14 





43 



















































CHART 15 



























































CHART 16 



45 











































































CHART 17 



46 



















































CHART 18 


Cttre^ro'Spis&l F^vex (acaiageeocct*) 

at' U. 5.N T. S.. Great .LaKta. lUiaoii 

104 * 1044 


•/ Ca**«. Hat** f*t !••• p«f Mantk 
•isi B«a ^ lata* 


; Control 


TT««t*4 ft~i-..4 Ii^.aal.UM> 



47 








































































Table 12. — Disease rates in recruit camps for December 19^S, 
January and February 19^J^ 


Disease 

Total cases 

Rate/1000 

Treated * 

Untreated 

Treated 

Untreated 

Upper respiratory complaints at sick call. 

40,363 

25,599 

595 

704 

Admitted to dispensaries with upper respiratory infec¬ 
tions .. 

2,886 

3,897 

42.7 

107 

Admitted to hospital with all respiratory infections. 

398 

2,621 

5.9 

72.0 

Scarlet fever . 

84 

441 

1.2 

12.1 

Tonsillitis or pharyngitis-- 

601 

2,145 

8.9 

59.1 

Pneumonia, lobar or broncho.... 

99 

154 

1.5 

4.2 

Cerebrospinal fever (mening.) . 

2 

24 

0.0 

0.7 

Rheumatic fever_... 

10 

51 

0.1 

1.4 

Otitis media, acute... 

119 

369 

1.8 

10.1 

Sinusitis, acute. . 

38 

81 

0.6 

2.2 


* Treated signifies groups receiving prophylaxis; untreated signifies control groups receiving no prophy¬ 
laxis. This terminology is used throughout these tables. 


Table 13. —Disease rates in service school for December 19 J ^3 
' and January 1944 


Disease 

Total 

cases 

Rate/1000 

Treated 

Untreated 

Treated 

Untreated 

Upper respiratory complaints at sick call. 

2,042 

7,225 

274 

838 

Admitted to dispensaries with upper respiratory in¬ 
fections. 

60 

419 

8.1 

48.5 

Admitted to hospital with all respiratory infections. 

128 

697 

17.2 

80.8 

Scarlet fever.. 

36 

216 

4.8 

25.0 

Tonsillitis or pharyngitis_ .. 

27 

265 

3.6 

30.7 

Pneumonia, lobar or broncho. 

1 

29 

0.1 

3.4 

Cerebrospinal fever (mening.)... 

0 

6 

0.0 

0.7 

Rheumatic fever_ _ 

8 

38 

1.1 

4.4 

Otitis media, acute... 

33 

118 

4.4 

13.7 

Sinusitis, acute__ 

4 

5 

0.5 

0.6 


48 


















































CHART 19 





































































































































































































































































































CHART 20 







50 















































































tive for beta hemolytic streptococci, and that 45.8 percent of 162 men with 
catarrhal fever not taking prophylactic sulfadiazine had positive cultures. 

Effect of Prophylactic Sulfadiazine on Incidence of Pneumonia 

Practical considerations have made separation of pneumonia into virus 
and bacterial etiology difficult. As a result, all pneumonia cases have 
been grouped together, regardless of their etiology. For every case oc¬ 
curring in a treated recruit there were 2.8 cases among the untreated re¬ 
cruits. The results are similar in the Service School. Cliart 17 shows 
th^ weekly incidence in the recruit camps and Service School. 


Effect of Prophylactic Sulfadiazine on Incidence of Cerebrospinal Fever 
(Meningococcic) 

In this disease sulfadiazine as a prophylactic agent was most success¬ 
ful. During the period under discussion there were 3 cases of meningitis 
among the treated groups as compared with 32 cases among the control 
groups. Careful questioning of the 3 patients revealed that only 1 of the 
patients had received any sulfadiazine, and this man’s blood sulfonamide 
level was less than 0.2 mg. percent. This difference is emphasized when 
these absolute numbers of cases are reduced to rates, because the treated 
groups are approximately twice as large as the control groups (chart 18). 


Effect of Prophylactic Sulfadiazine on Incidence of Rheumatic Fever 

Because of the antecedent role of the streptococcus in the causation of 
rheumatic fever, it is clear that the complete effect on the incidence of 
rheumatic fever will not be evident until some subsequent date. Despite 
this, for each case occurring among the treated recruits there have been 
14 among the untreated. Chart 19 shows the weekly course of rheumatic 
fever incidence at the Training Center during the period under discussion. 

Tables 12 and 13 summarize the incidence of the diseases previously 
mentioned and the number of hospital and dispensary admissions in the 
treated and untreated groups. Chart 20 is a graphic presentation of 
these values. 


Laboratory Studies 

Observations on Blood Suljadiazine Levels .—A blood sulfadiazine level 
was obtained for each patient admitted to the dispensaries and hospital 
with any respiratory infection. A group of healthy men receiving sulfa¬ 
diazine prophylactically was used to obtain control blood levels. Table 

51 


14 shows the relationship between the number of positive throat cultures 
and blood sulfadiazine levels in the treated group. If one divides the 
number of positive throat cultures by the total number of throat cultures 
at a given blood sulfonamide level, it becomes evident that the percentage 
of positive throat cultures is not related to that level. 


Table 14. —Incidence of positive {hemolytic streptococcus) throat cultures 
in relation to sulfadiazine blood level in men admitted to dispensaries for 
upper respiratory infections 



52 





















































Table 15 demonstrates the mean, median, standard deviation, and range 
of the blood sulfadiazine levels obtained in patients and in well men re¬ 
ceiving sulfadiazine prophylactically. There was nO' significant differ¬ 
ence in the means of these groups. It can be concluded, therefore, that 
a low blood sulfadiazine level was not the important factor in the failure 
of sulfadiazine prophylaxis in these men studied, if we assume that the 
I blood level at the time of admission accurately reflects the blood level at 
the time the infection was contracted. 

In an effort to determine whether there was an accumulation of sulfa¬ 
diazine in the blood after prolonged administration, the blood sulfadiazine 
levels were studied in successive groups who had been receiving the drug 
for 1, 2, 3, 4, and up to 31 days. Chart 21 shows the high, mean, and 
low levels. It can be seen that there is no accumulation of sulfadiazine 
in the blood after 1 month of administration, and that the highest levels 
I are reached as early as the second day. It is also shown that the range 
[ between high and low levels is considerable. It is possible that an occa- 
i sional man might have taken more or less than the prescribed dose; this 
1 would account in part for the wide range in blood levels. Undoubtedly, 

' there is individual variation in the absorption and excretion of the drug. 


Table 15. —Comparison of blood sulfadiazine levels in patients who contracted 
respiratory infections and in men who remained well while taking 
prophylactic sulfadiazine 


Subjects tested 

Number 

of 

observa¬ 

tions 

Mean 

Mg.% 

Median 

Mg.% 

Standard 

deviation 

Mg.% 

Range 

Mg.% 

fJreen Bay patients 

2,961 

193 

1.5 

1.5 

1.1 

0.0-7.4 

Service School natients_ _ 

1.4 

0.9 

1.4 

0.0-6.8 

Well men._. 


56 

1.7 

1.9 

1.1 

0.0-4.0 


Table 16. — Summary of throat cultures taken from men admitted to disperi- 
saries and hospitals for upper respiratory infections 



Positive 

Negative 


Subjects 





Total 


Number 

Percent 

Number 

Percent 


Treated 

242 

7.7 

2,912 

92.3 

3,154 

Controls.—..... 

178 

52.3 

162 

47.7 

340 


53 





























CHART 21 



54 


V 































































































Table 17. — Streptococcus typings according to type and week 


Type 

December 
week ending 

January 
week ending 

February 
week ending 

March 
week ending 

Total 

4 

11 

18 

25 

1 

8 

15 

22 

29 

5 

12 

19 

26 

4 

11 

18 

1 

1 

0 

6 

0 

4 

0 

5 

4 

6 

6 

3 

2 

3 

3 

0 

0 

43 

2 

0 

0 

1 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

1 

3 

0 

1 

5 

3 

11 

3 

2 

11 

9 

6 

0 

2 

1 

7 

0 

0 

61 

5 

1 

5 

6 

1 

2 

3 

3 

2 

6 

5 

3 

3 

2 

7 

0 

0 

49 

6 

0 

1 

2 

2 

3 

4 

0 

3 

0 

3 

0 

1 

0 

1 

0 

0 

20 

9 

0 

0 

0 

0 

0 

0 

0 

1 

0 

0 

0 

0 

0 

0 

0 

0 

1 

12 

0 

0 

2 

1 

0 

0 

1 

1 

1 

0 

0 

0 

1 

0 

0 

0 

7 

15 

0 

0 

0 

0 

1 

0 

0 

0 

0 

0 

0 

1 

0 

0 

0 

0 

2 

17 

1 

8 

4 

5 

6 

6 

1 

8 

6 

4 

4 

4 

3 

7 

0 

0 

67 

18 

0 

1 

0 

0 

0 

0 

0 

0 

0 

0 

9 

0 

0 

0 

0 

0 

1 

19 

0 

5 

5 

1 

3 

1 

2 

13 

5 

12 

5 

0 

1 

11 

0 

0 

55 

24 

0 

1 

0 

0 

0 

0 

1 

0 

0 

1 

0 

0 

1 

0 

0 

0 

4 

26 

0 

0 

1 

0 

1 

0 

0 

0 

1 

1 

2 

0 

0 

0 

0 

0 

6 

30 

0 

1 

0 

0 

0 

1 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

2 

32 

0 

0 

0 

0 

1 

1 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

2 

33 

0 

0 

0 

0 

0 

0 

0 

1 

0 

0 

0 

0 

0 

0 

0 

0 

1 

36 

0 

0 

0 

0 

1 

1 

0 

0 

0 

2 

0 

1 

0 

0 

0 

0 

5 

39 

0 

0 

1 

0 

1 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

2 

41 

0 

0 

1 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

1 

43 

0 

0 

0 

0 

0 

0 

0 

0 

0 

1 

0 

0 

0 

0 

0 

0 

1 

44 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

1 

0 

0 

0 

1 

46 

0 

0 

0 

0 

1 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

1 

Total 

3 

23 

34 

13 

35 

20 

15 

44 

34 

41 

17 

14 

13 

27 

0 

0 

333 


Table 18. —Streptococcus typings according to regimental areas 
December, January, February, and March 


Type 

Number of regimental area 

Service 
school and 

O. G. U. 

Total 

21st 

23d 

25 th 

27th 

29th 

31st 

8th 

10th 

12 th 

1 

4 

0 

2 

7 

3 

3 

4 

1 

1 

18 

43 

2 

0 

0 

0 

0 

0 

1 

0 

0 

0 

0 

1 

3 

1 

2 

9 

6 

2 

2 

10 

5 

8 

16 

61 

5 

5 

5 

7 

19 

1 

1 

0 

0 

1 

10 

49 

6 

3 

1 

4 

4 

0 

0 

0 

0 

2 

6 

20 

9 

0 

1 

0 

0 

0 

0 

0 

0 

0 

0 

1 

12 

2 

0 

0 

1 

2 

0 

0 

0 

0 

2 

7 

15 

0 

0 

1 

0 

0 

0 

0 

0 

0 

1 

2 

17 

3 

9 

7 

10 

1 

2 

3 

6 

5 

21 

67 

18 

0 

0 

0 

0 

0 

0 

0 

0 

0 

1 

1 

19 

2 

2 

4 

1 

1 

4 

8 

4 

1 

28 

55 

24 

0 

0 

0 

1 

0 

1 

0 

0 

0 

2 

4 

26 

1 

0 

0 

1 

0 

0 

4 

0 

0 

0 

6 

30 

0 

0 

0 

e 

0 

0 

0 

0 

0 

2 

2 

32 

0 

0 

0 

0 

0 

0 

0 

0 

0 

2 

2 

33 

0 

0 

0 

0 

1 

0 

0 

0 

0 

0 

1 

36 

0 

0 

0 

0 

1 

0 

0 

0 

0 

4 

5 

39 

0 

0 

0 

0 

0 

0 

1 

1 

0 

0 

2 

41 

0 

0 

0 

0 

0 

1 

0 

0 

0 

0 

1 

43 

0 

1 

0 

0 

0 

0 

0 

0 

0 

0 

1 

44 

0 

0 

0 

0 

0 

0 

1 

0 

0 

0 

1 

46 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

1 

Total 

21 

21 

34 

50 

12 

15 

31 

18 

18 

113 

333 


55 




























































Observations Regarding Throat Cultures .—A throat culture on blood 
agar was taken of all the patients with respiratory infections admitted to 
the dispensaries and hospital. Control cultures were taken of a series 
of upper respiratory admissions in the control camps. Table 16 demon¬ 
strates the remarkable reduction in the percentage of positive beta hemo¬ 
lytic streptococcus throat cultures in the treated men as compared with 
the controls. An analysis of all group A typings completed to date is 
shown in tables 17, 18, and 19. 

Types 17, 19, 3, 5, 1, and 6 were most frequently isolated in the order 
named. Type 17, which was most prevalent, occurred 67 times or in 
20 percent of the entire group. 

It becomes apparent that a large number of types have been endemic 
throughout the entire station and throughout the entire period of time 
indicated. No one type has reached epidemic proportions. It is to be 
seen that any of the commonly isolated types has been found in association 
with a wide variety of clinical entities. In this analysis it is assumed that 
all types of streptococci are grown, isolated, and typed with equal facility. 


Table 19. —Streptococcus typings according to diagnosis, Green Bay, service 
school, and controls, December, January, February, and March 



Diagnoses 

Type of Group A hemolytic streptococcus 

Scarlet 

fever 

Pharyngitis 

and 

tonsillitis 

Catarrhal 

fever 

1 , .. 

1 

26 

13 

9. 


1 


2 

28 

25 

R . ...... 

17 

22 

6.. 


11 

8 



1 

12 


2 

3 

15 


2 

17 

4 

24 

33 

18 


1 

1<) 

2 

22 

26 

2 

9A 


2 

2fi 


2 

2 

-30. 


2 


32. 



2 

33. 



1 

3fi 


3 

2 



1 

1 

41.... .. 



1 




1 

44 


1 


46. 



1 






56 

































CHART 22 



57 


























An Estimation of Number of Man-Days Saved as Result of Institution of 
Sulfadiazine Prophylaxis Program 

The actual number of sick days spent in the wards of the dispensaries 
and hospital from 1 December 1943 to 29 February 1944 was counted for 
both the treated and untreated men. By subtracting these two figures 
and assuming the same morbidity rate for the two groups, and correcting 
for the difference in populations, an estimation was made of the man-days 
saved. 

By using the aforementioned method, it has been estimated that 45,359 
man-days were saved from 1 December 1943 to 29 February 1944 by the 
sulfadiazine streptococcus prophylaxis program. Chart 22 graphically 
represents the number of sick days lost per thousand recruits in the 
treated and control groups for December, January, and February. It is 
seen that for every 1 man-day lost in the treated group, there were more 
than 4 man-days lost in the control group. 

For this same period, 384 man-days have been lost from untoward sul¬ 
fadiazine reactions. Calculated from Bureau of Medicine and Surgery 
data on the average time spent on the Sick List because of respiratory 
infections and their sequelae, our saving during this controlled study totals 
72,776 man-days. 

Untoward Reactions: Dermal Reactions in White Enlisted Personnel 

From 1 December 1943 to 31 March 1944 inclusive, a total of 654 
dermal reactions was observed among the white enlisted personnel who 
were taking prophylactic sulfadiazine. Of these, 466 were seen in re¬ 
cruits in the Green Bay area giving a rate of 5.6 per thousand, and 43 
were observed among enlisted personnel in Service School giving a rate 
of 1.5 per thousand. The men in Green Bay area and part of the men 
in Service School were on the program during most of the prophylaxis 
period. These 2 groups thus give the most accurate reaction rates. The 
remaining rashes occurred in men who were on the program for only 2j4 
weeks, and these have not been included in the computation of the rates. 

To identify true sulfadiazine reactions more clearly, all men except 
those who have been transferred were retested with sulfadiazine at a later 
date. To retest, after the initial reaction, the men were not given sulfa¬ 
diazine for a period of from 7 to 21 days, and they were then given 0.5 
gm. or 1 gm. of sulfadiazine daily for 3 days under close observation. 
When secondary reactions occurred, the time of onset and type of reaction 
were noted, and the men were permanently removed from the program. 
If no secondary reactions occurred, the men were again included in the 
program and no subsequent reactions were observed. A summary of the 
dermal reactions observed in enlisted personnel is given in table 20. 


58 


Table 20.— Dermal reactions in white enlisted personnel 



59 





























































A primary dermal reaction is defined as the initial reaction observed 
while prophylactic sulfadiazine is being given. Primary dermal reactions 
are classified as (a) morbilliform; (b) erythematous; (c) urticarial; (d) 
papular; (e) photosensitization; (f) fixed eruption; (g) exfoliative der¬ 
matitis; (h) purpura. 

Morbilliform Reactions .—Morbilliform reactions were by far the most 
common dermal reactions as they made up 38.7 percent of the total pri¬ 
mary rashes. The typical eruption of this type is fine morbilliform rash 
more or less generalized except for the face, and showing confluent lesions 
over the back and extensor surfaces of the extremities. Only about one- 
third of the cases have involvement of the face. In some cases, the rash 
is more generally confluent, even over the trunk, with only small scat¬ 
tered clear areas intervening. In a few instances, the rash involves solely 
the extremities, or shows sparse lesions only on the trunk. This rash 
closely resembles German measles with which it is easily confused. When 
the rash is blotchier and confluent and accompanied by fever, the dif- 
ferentation from “red” measles is sometimes difficult. The most char¬ 
acteristic feature of these rashes is the bright vivid pink of the lesion as 
contrasted with duller red lesions of measles and German measles. Other 
features usually present are a moderate generalized lymphadenopathy, mild 
temperature elevation of 99“ F. to 101° F., pruritis, a facial flush, and 
injected conjunctivae. Because the rash sometimes cannot be conclu¬ 
sively differentiated from German measles the following helpful diagnostic 
points are offered: 

1. The bright vivid pink color of the lesions. 

2. The face is not usually involved. 

3. There is frequent temperature elevation above 100° F. which is 
uncommonly seen in German measles. 

4. The postauricular glands are rarely as large as in German measles. 

5. There is frequent predominance and confluence of the lesions on the 
extensor surfaces of the extremities. 

6. There is frequent pruritis. 

7. The entire rash usually appears simultaneously. In German measles, 
the rash typically appears on the face and spreads downward progres¬ 
sively. This is a helpful point when the rash involves the face. In 
doubtful cases, isolation of the patient in sickbay for a few hours to ob¬ 
serve progression of the lesions was found to be helpful. 

As for the differentiation from measles, these are the most reliable 
diagnostic points: 

1. There is no preceding history of coryza and cough. 

2. There is an absence of Koplik’s spots. 

3. Conjunctival injection is common but coryza and photophobia are 
rare. 

4. The lesions are pink. 


60 


5. There is no downward progression of lesions. 

6. Pruritis is present. 

7. Temperature elevations from 102“ F. to 104“ F., as seen in measles, 
are uncommon. 

The rashes develop within an average period of 15 days of sulfadiazine 
prophylaxis. The range was from 1 to 40 days, although the majority 
of cases occurred consistently in the 7 to 21 day period. 

Erythemas .—The erythematous eruptions comprised 22.6 percent of 
the total primary rashes. The erythemas were generally of 4 different 
types. The mildest type is a fine red macular rash involving mainly the 
trunk. The second type is a blotchy erythema scattered mainly over the 
trunk and sometimes over the extremities. The third type, a rather 
uncommon one, is characterized by discrete circular bright red macules, 
varying from 1 cm. to several centimeters in diameter, which are scattered 
over both the trunk and extremities. The last and most severe type is 
a diffuse erythema, usually covering the face, trunk, and extremities. As 
may be seen, the erythemas have a predilection for the trunk, but, with 
increasing severity, spread to the extremities and face as well. Con¬ 
comitant features, especially in the diffuse erythemas, are a sudden onset, 
acute prostration, chills, intensely injected conjunctivae, a diffusely in¬ 
jected pharynx, injected tympanic membranes, and frequent temperature 
elevations to 102“-103“ F. and higher. 

These types of reactions, particularly in diffuse erythemas, must be 
differentiated from scarlet fever. Desquamation has been observed in 
some of the more severe erythemas from sulfadiazine. Because some 
of the scarlet fever patients may be treated with sulfonamides, it is imper¬ 
ative to make a correct diagnosis. Differentiating characteristics of sul¬ 
fadiazine erythemas are as follows: 

1. Sore throat, rare. 

2. Intense conjunctival injection. 

3. Intense facial erythema and absent circumoral pallor. 

4. Erythema is diffuse and not punctate in character. 

5. No predilection for the folds or thin-skinned areas. The rash often 
is less intense over these areas. 

6. Absence of punctate appearance of the soft palate and uvula. 

The average period of time under sulfadiazine treatment before the 
rash developed was 13 days with a range of from 5 to 21 days. 

Urticarias .—^Urticarias comprised 21.4 percent of the total rashes ob¬ 
served. There was nothing characteristic either in type or distribution 
to differentiate them from urticarias from other causes. They were 
sometimes associated with nasal coryza and edema of the hands, face, or 
feet. As usual, they were markedly pruritic and not associated with 
fever. Some of the morbilliform and papular rashes had scattered areas 

61 



of urticaria as well. Adrenalin or ephedrine sulfate usually relieved the 
rash and symptoms. 

These men had been taking sulfadiazine for an average period of 16 days 
with a range of from 1 to 56 days. There was wide variation between 
individual cases in the length of time that sulfadiazine was taken. 

Papular Rashes .—^The papular rashes constituted 15 percent of the 
total rashes. These rashes are of 2 distinct types and are the most easily 
diagnosed of the sulfadiazine eruptions. One type is bright pink and the 
other, deep red. The lesions vary in size from 1 mm. to 2 mm. to con¬ 
fluent areas of several centimeters in diameter; they are irregular in out¬ 
line, and are scattered usually over both trunk and extremities. The 
confluent areas are common over the upper part of the chest and back, 
and especially, over the extensor surfaces of the extremities. In the re¬ 
cruits, the lesions over the areas covered by boots are often purpuric, 
presumably from pressure. Pruritis is frequently intense. About half 
the men had temperatures of from 99° F. to lOF F. 

The men were taking sulfadiazine for an average period of 13 days 
with a range of from 5 to 25 days. Most of the cases fell within the 
13-day period. 

Photosensitisation .—There have been observed 15 cases, or 2.3 percent 
of the total, in which the skin manifestations appeared only in areas ex¬ 
posed to sunlight, such as the face, neck, and the dorsa of the hands and 
wrists. These are thought to be examples of photosensitization. In 
general, the rashes are either erythematous or of a pink papular type. 
In all ckses there were facial rashes and in two-thirds similar involve¬ 
ment of the dorsa of the hands and wrists as well. There is usually an 
associated edema, burning sensation, and pruritis of the areas concerned. 
Those patients with erythema had secondary exfoliation. 

These patients had been taking prophylactic sulfadiazine for an aver¬ 
age period of 16 days with a range of from 2 to 28 days. 

Fixed Eruption .—These rashes (six) formed 0.9 percent of the total 
reactions. All patients gave histories of reactions over the same areas 
from previous sulfonamide therapy. Apparently, the previous sulfona¬ 
mides caused local increased tissue sensitivity, so that on subsequent 
sulfadiazine ingestion a rash occurred at the same sites. Two of the 
patients had been treated with local sulfathiazole ointment for bums on 
the forearms and one for impetigo of the face. These three developed a 
local sulfathiazole dermatitis over the same areas at that time. The other 
three patients had been taking either sulfathiazole or sulfadiazine orally, 
and developed localized scattered eruptions over the trunk and extrem¬ 
ities. All six patients reacted again within a few hours after the initial 
gram of sulfadiazine on the streptococcus program. 

Fixed eruptions are either of a papular, erythematous, or eczematoid 
nature. There are probably more fixed eruptions than are generally 

62 


Table 21 .,—Summary of data in cases of exfoliative dermatitis 


V 

E 

o 

V 

a 

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CQ 

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T3 

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^ *s 

£ S 

s 

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£ 

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T3 

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««-« ^ 

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63 






























































































recognized. It was observed that some of the men retested developed 
secondary lesions at the sites of pigmentation residual from the primary 
lesions. These, however, were not included as fixed eruptions. 

Generally, therefore, fixed eruptions represent local tissue hypersensi¬ 
tivity which is manifested by secondary reactions within a few hours. 
The duration of this hypersensitivity is not known. In this series, the 
first reactions occurred in from 2 to 18 weeks before the secondary cases. 

Exfoliative Dermatitis .—For convenience, the five cases of exfoliative 
dermatitis occurring in the white and the three cases occurring in the 
Negro personnel are considered together. Table 21 shows the salient 
clinical and laboratory features. 

Table 21 shows that two out of three patients who received sulfadiazine 
therapy after the appearance of skin manifestations died. Four out of 
five of the men who were treated only with supportive measures made 
a complete recovery. 

Because of the wide variation in the presenting signs and symptoms 
in cases that subsequently proved to be exfoliative dermatitis, the follow¬ 
ing admission diagnoses at the hospital were made: catarrhal fever, 
chickenpox, German measles, and scarlet fever. 

The original skin lesions rapidly progressed to secondary vesicles and 
bullae which coalesced. Subsequent to this, a more or less generalized 
exfoliation of the skin and mucous membranes occurred. In addition, 
there were an acute febrile course, purulent conjunctivitis, purulent nasal 
discharge, and necrotic sloughing lesions of the lips, mouth, and throat. 
The leukocyte counts were usually increased and a hypochromic anemia 
often developed. Therapy included plasma and whole blood transfusions, 
intravenous saline and dextrose solutions, penicillin, and minute attention 
to the local lesions. 

Purpura .—Only two cases of eruptions with a considerable purpuric 
component were seen. Fairly marked purpura developed in the lesions 
of a previous maculopapular rash over the trunk and extremities, the pur¬ 
pura coming 1 or 2 days after the original rash. There were, however, 
many cases in which small petechial hemorrhages or mild purpura oc¬ 
curred with rashes which were predominantly of another type. Such 
purpuras were common over areas of pressure, such as over the areas 
covered with the boots. 

Dermal Reactions in the Negro Enlisted Personnel 

A summary of these dermal reactions is in table 22. Although there 
was a relatively high incidence of exfoliative dermatitis, the absolute 
number of reactions among Negro enlisted personnel was small. Be¬ 
cause this group had been taking prophylactic sulfadiazine for only 2^ 
weeks, no conclusions can be drawn. 


64 



Table 23. —Summary of data in 5 cases of granulocytopenia 


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7 bands, 47 lymphocytes, and 4 monocytes. 







































Untoward Reactions on the Hematopoietic and Urinary Systems 

Up to date there have been six cases of granulocytopenia, four of 
which were fatal. Of the four fatal cases, three were studied in the 
wards, and one patient died at home while on “boot” leave. Unfortu¬ 
nately, the circumstances of the death in the last case were not obtain¬ 
able. Table 23 shows the salient clinical and laboratory features in the 
three fatal cases of granulocytopenia and in the two cases in which the 
patients recovered. These five cases presented several interesting fea¬ 
tures : There was no patient under the age of 20; the amount of sul¬ 
fadiazine received was not large in any case; the blood sulfadiazine level 
in no case reached unusual levels. It is to be noted that three of the 
five patients received varying amounts of sulfadiazine in addition to the 
regular 1 gm. daily prophylactically. 

At the beginning of the program no examinations of white cell counts 
and of urine specimens were made. Subsequent events have shown that 
even such a small dose as 1 gm. a day can have a suppressing action on 
the leukocytes. Because of this, it was decided to take a sampling of 
leukocyte counts among men who had been receiving prophylactic sulfa¬ 
diazine longer than 3 weeks. At the same time it was decided to examine 
a similar number of urine specimens microscopically for hematuria. A 
total of 650 leukocyte counts and urinalyses were done among the white 
recruits, and 250 leukocyte counts and urinalyses among the Negro re¬ 
cruits. The results of the blood sampling appear in table 24. 

The question arises whether these differences between the leukocyte 
counts of white and Negro patients are racial or due to a greater sensitivi¬ 
ty on the part of the Negro to the leukocyte-suppressing action of sulfadia¬ 
zine. In an effort to answer this question, leukocyte counts were taken of 
a random sample of 125 Negroes on first reporting at the Training Center 
for duty, before receiving any sulfadiazine. These Negroes had a wide 
distribution in respect to age (range 17 to 36 years), degree of racial 
mixture, home state, and occupation. The mean of these counts was 
6,940, and the distribution was as follows: 


Percent 


Above 10,000 . 1.6 

5,000-10,000 . 89.6 

4,000-5,000 . 8.0 

Under 4,000 . 0.8 


Two Negroes and one white man were found to have a leukocyte count 
below 4,000. In all three cases the suppression occurred mainly in the 
granulocytic series. Each man was immediately withdrawn from the 
program. After 3 days, one attained a normal count; after 7 days, the 
second had a normal count; there is no information for the third person 
since he was on “boot” leave soon after the discovery of leukopenia. 

66 








There has been no case of hematuria without associated evidence of 
urinary tract infection in the 900 urine specimens examined. 


Unclassified Reactions 


^ These 20 cases of unclassified reactions, representing 3 percent of the 
I total, were reactions other than dermal or hematopoietic. A list of these 
reactions includes: 

' chills 
fever 
pruritis 

Fairly Common ^ flushed face 

burning eyes with conjunctival injection 
cyanosis of hands (although commonly observed, this 
is not considered an untoward reaction) 

{ edema of hands, feet, or face 
headache 
anorexia 
vertigo 


Rare 


' arthralgia 
nausea 
vomiting 
i backache 

sore throat with pharyngeal injection 

coryza 

mild asthma 


Table 24. — Leukocyte counts in white and Negro recruits receiving 
prophylactic sulfadiazine 



Whites 

Negroes 

Total number of counts___ 

650 

250 

Average (mean)... 

8,064 

13.1 

7,138 

Percent above 10,000.... 

9.2 

Pprepnt hfitwefin 5,000 and 10,000 

82.9 

79.2 

Percent below 5,000.. 

4.0 

11.6 

Percent below 4,000.. 

0.15 

0.8 




One case of jaundice was seen. A 21-year-old Negro, who had been 
taking prophylactic sulfadiazine for 2 weeks, negligently omitted the drug 
for 1 week and became acutely ill with chills, fever, and urticaria 6 hours 
after the ingestion of 1 gm. of sulfadiazine. He subsequently developed 
nausea, vomiting, facial edema, jaundice, an enlarged liver, and a vesicu¬ 
lar rash of the face. After a hospital course of 4 weeks, he is apparently 
recovering. The etiologic agent of the liver disturbance is not definite, 
although prophylactic sulfadiazine cannot be excluded. 

Sensitivity and Retesting for Sensitivity 

Table 20 shows the frequency of secondary reaction types elicited by 
retesting. Secondary reaction is defined as a reaction appearing on re- 


67 












































testing. There are five important clinical facts that can be derived from 
the secondary dermal reactions: 

1. The secondary eiythematous rashes were by far the most common 
secondary dermal reactions as they constituted almost two-thirds of the 
total. 

2. Exclusive of the secondary morbilliform rashes, the other secondary 
dermal reactions occurred within an average period of 4 hours after the 
initial retest dose. The range was from 1 tO' 10 hours. 

3. The secondary morbilliform rashes apparently developed more 
slowly as the average reaction time was 18 hours (range from 5 to 36 
hours) after the first retest dose. 

4. Urticarias seem to be an uncommon type of reaction to sulfadiazine, 
as only 3 of 92 primary urticarias had secondary reactions on retesting. 

5. The secondary morbilliform and papular rashes all had primary 
rashes of either of these two types. None had primary erythemas or 
urticarias. 

Unclassified secondary reactions were essentially the same as those 
described previously under that heading. 

Of the 249 men who were retested without secondary reactions, many 
were thought to have true primary drug reactions. There are several 
possible explanations. First, during the 3-week period, when 0.5 gm. of 
sulfadiazine was used as a retest dose, only 8 of 58 men (14 percent) gave 
a secondary reaction; whereas during the period when 1 gm. of sulfadia¬ 
zine was used, 154 or 356 men (43 percent) reacted positively. It can 
be seen, therefore, that the size of the test dose is a factor in the develop¬ 
ment of secondary reactions. Second, it is also possible that in some of 
the men who did not react to the retest dose, there was a drop in sensi¬ 
tivity during the interval between the primary reaction and retesting. 
Third, diagnostic errors in primary reactions undoubtedly comprised a 
certain number of those who' did not react a second time. 

By sulfadiazine sensitivity we mean the innate or acquired ability of 
a person to react untowardly to sulfadiazine. In this program dermal 
reactions are taken as an indication of sensitivity. The manner in which 
these dermal reactions appeared can be divided into three classes: Into 
the first and largest class can be put those men who developed a rash only 
after having taken prophylactic sulfadiazine continuously for 5 or more 
days. Into the second class can be put those men who have taken their 
sulfadiazine interruptedly, with periods of from 4 to 28 days during 
which no drug was taken. This class is smaller in size than the first, 
but it is important from the standpoint of mass sensitization. In the 
third and smallest class are 22 men who developed a rash within a few 
hours after they took the initial dose of prophylactic sulfadiazine. Most 
of these men gave no history of previous contact with sulfonamides. 
These men may be considered to be innately sensitive or to have acquired 

68 


a sensitivity to sulfadiazine in an unknown manner. This class can be 
dismissed with the statement that it is unlikely that they acquired their 
sensitivity from our program. 

Class 1 .—Of the reactions observed in the Green Bay area between 

I December 1943 and 15 April 1944, 554 of the 597 have been placed in 
the first class. All patients had been taking sulfadiazine for at least 5 
days before they developed, a rash. Of this group 136 when retested 
developed a secondary rash. If permanent sensitivity to sulfadiazine is as¬ 
sumed in this class, then 1.5 men per thousand have been prevented from 
further use of sulfadiazine. 

Of the first class 208 when retested did not react with a secondary 
rash, and were returned to the prophylactic program without recurrence 
of dermal reactions. It may be assumed that these men had not been 
permanently sensitized to sulfadiazine in prophylactic doses. 

Of the first class 210 were not retested because of inaccessibility. If 
this group had a similar rate of positive reactions to retesting, then an 
additional 136 or 1.5 men per thousand have been prevented from further 
sulfadiazine therapy. 

Class 2 .—Four large groups of men have been under close observation 
during the resumption of sulfadiazine prophylaxis after varying periods 
of interruption. 

1. In 1,400 recruits who had been taking sulfadiazine prophylaxis for 
3 weeks or longer, sulfadiazine was withdrawn for 7 days. On resump¬ 
tion of the drug, no reactions were observed within a period of 7 days. 

2. Service School, Group I, consisting of 3,580 men who had been 
taking sulfadiazine for 2 months with reaction rates of 1.1 men per 
thousand per month was withdrawn from the program during the month 
of February. On resumption of sulfadiazine prophylaxis in March a 
reaction rate of 1.9 per thousand was observed. Service School, Groups 

II and III, on the program in February and March gave a reaction rate 
of 1.5 per month. 

3. From recruit camps, 27,438 men having taken sulfadiazine prophy- 
lactically longer than 1 week have been withdrawn from the program 
from 9 to 15 days by virtue of “boot leave.” On returning from “boot 
leave,” they were again included in the program while being held in the 
out-going unit. A primary reaction rate of 0.87 per thousand was ob¬ 
served. 

4. In a group of recruit camps, sulfadiazine prophylaxis was inter¬ 
rupted for 4 days. On returning to the program, 21 primary reactions 
were observed in 24,472 men, giving a rate of 0.85 per thousand. 

It must be admitted that some are sensitized to sulfadiazine by the 
ingestion of 1 gm. daily for 7 or more days; however, the over-all rate 
does not exceed the sum of the rates in classes 1 and 2 or 3.9 per thousand. 


69 


Relationship of Sulfadiazine Blood Levels, Leukocyte Counts and 
Immunizations to Dermal Reactions 

In 300 men with primary dermal reactions, the mean blood sulfadiazine 
level was 1.4 mg. percent with a range of 0.0 percent to 4.2 mg. percent. 
This mean is not significantly dififerent from the mean of blood sulfadia¬ 
zine levels obtained on admission for respiratory disease and in well con¬ 
trols. Of these reactions 47 had blood levels of 0.1 mg. percent or less. 
It becomes apparent that the development of dermal reactions does not 
depend on the presence of a high sulfadiazine blood level. 

One hundred cases of dermal reactions to sulfadiazine were found to 
have admission leukocyte counts as follows: 


Normal. 5,000- 10,000 50 percent 

Above normal..10,000-or more, 41 percent 

Below normal. 4,000 - 5,000 6 percent 

Less than 4,000, 3 percent 


All recruits within a 5-week period are immunized against typhoid, 
smallpox, yellow fever, and tetanus. The role of these immunizations 
as multiple sensitizers is unknown, but it should be pointed out that the 
over-all rate for dermal reactions in recruits is 4 times as great as the 
over-all rate in Service School personnel who received no immunizations. 
Summary 

1. One gram of sulfadiazine was administered daily as a prophylaxis 
to 188,000 enlisted personnel from December 1943 to April 1944. 

2. This prophylactic measure proved highly effective in reducing the 
incidence of respiratory diseases. 

3. Severe respiratory tract infections requiring hospitalization were 
reduced from 80 to 90 percent. 

3. The incidence of cerebrospinal fever (meningococcic) was reduced 
98 percent. 

5. The incidence of streptococcal infections was reduced 85 percent. 

6. The rheumatic fever rate fell strikingly. The ratio of cases occur¬ 
ring in areas receiving prophylaxis and control areas was 1 to 14. 

7. There was also a significant but less impressive reduction in the 
incidence of catarrhal fever, pneumonia, otitis media, and sinusitis. 

8. The incidence of mild respiratory complaints fell markedly following 
the institution of prophylaxis but rose to the control group level in 
February. 

9. The ingestion of 1 gm. of sulfadiazine daily afforded a well main¬ 
tained blood level of from 1 mg. to 2 mg. percent. 

10. Approximately 0.39 percent of Naval personnel with this blood 
level developed drug reactions. 

11. A few of these reactions were severe. Seven deaths occurred; how¬ 
ever, only one of these was attributable solely to prophylaxis. 

12. Further utilization of mass sulfadiazine prophylaxis is indicated, 
but only when initiated and supervised by experienced medical officers. 

70 





Report 4 


The Streptococcal Control Program 

U. S. Naval Training Center, Sampson, New York 

From Epidemiology Unit 12* 


In early November 1943 the Bureau of Medicine and Surgery, through 
the Division of Preventive Medicine, directed that a Streptococcal Con¬ 
trol Program be inaugurated and carried on at the United States Naval 
Training Center, Sampson, New York. At this time, it was decided to 
include in this program only the recruit areas of the station, which con¬ 
sisted of five units, each with facilities for approximately 5,000 men. The 
recruits of three units were to receive 1 gm. of sulfadiazine daily per. man, 
beginning 1 December 1943. The remaining two units were to serve as 
control. The administration of this program was delegated to Epidem¬ 
iology Unit 12, which at that time consisted of two' medical officers and 
five hospital corpsmen. It was later augmented by the addition of one 
medical officer, one bacteriologist, and two waves. 

Administration 

Edwards, Farragut, and Gilmore Units were selected as the areas to 
receive chemoprophylaxis. Callaghan and Dewey Units served as con¬ 
trols. Accurate daily records were kept of all patients with respiratory 
diseases seen at sick call or admitted to dispensary sickbay or the hos¬ 
pital or both. In addition to this, an epidemiology medical officer daily 
visited each recruit-unit dispensary and the hospital to confirm diagnoses 

♦Participants: Nicholas D. Lill, Lieutenant Commander (MC) USNR; 
Francis M. Quinn, Lieutenant (MC) USNR; George J. Ravit, Lieutenant (MC) 
USNR; Harvey C. Upham, Lieutenant (jg) H-V(S) USNR. 

Assistants: F. A. Rinehart, PhMlc; 1. A. Weaver, PhMlc; Hugh Hanson, 
PhMlc; Harold H. Dunn, PhMlc; Thomas H. Vanderhoof, PhMlc; Herbert T. 
Webster, PhM3c; Andreas G. Papandreou, PhM3c; Ann A. Caruso, PhM3c; George 
A. Amundson, PhMlc; Henry S. Ellison, Jr., PhMlc. 


71 





in all cases of respiratory diseases. Throat cultures were taken of all 
patients with frank or probable streptococcal diseases, including scarlet 
fever, tonsillitis, pharyngitis, erysipelas, otitis media, mastoiditis, and 
sinusitis. In cases of meningococcal infection, blood cultures, naso¬ 
pharyngeal cultures, and spinal fluid cultures were taken whenever 
possible. 

Blood samples were taken for the determination of blood sulfadiazine 
levels from all patients with frank or probable streptococcal or menin¬ 
gococcal disease in the treated areas. Beta hemolytic streptococci recov¬ 
ered from the throat flora were isolated in pure culture, transferred to 
miniature blood agar slants in Kahn tubes and shipped to the Strepto¬ 
coccus Typing Center at the National Naval Medical Center for grouping, 
typing, and sulfonamide-fastness studies. 

In order to establish a preliminary base line, every phase of the pro¬ 
gram, except the drug administration and culture studies, was begun on 
Monday, 22 November 1943. Data were collected and rounds made 
daily through 30 November. On 1 December every recruit in Edwards, 
Farragut, and Gilmore Units began to take two 0.5 gm. tablets of sulfa¬ 
diazine daily at approximately 1300. The dispensing of tablets was under 
the direct personal supervision of each company commander and company 
clerk. A check-off list insured that each man received his two tablets, 
and he was required to swallow them with water in the presence of the 
company commander. No one was excused from taking the drug unless 
he possessed a certificate from the medical officer of his unit indicating 
that he was sensitive to sulfonamide. 

During a 4-month period, 1 December 1943 to 1 April 1944, sulfa¬ 
diazine was given prophylactically in this program to 63,392 persons; 
the number of days each received the drug varied from 1 day, in a small 
group of hypersensitive persons, to 45 days. The average daily popula¬ 
tion taking the drug varied from 12,358 in December 1943, when only 
three recruit areas were receiving chemoprophylaxis to 27.,674 in March 
1944, when the program was extended to include one additional recruit 
area, the Service Schools and the Ship’s Company. 

Laboratory Studies 

Bacteriology .—Throat cultures were taken in all cases in which the 
diagnosis of streptococcal infection was made in both the treated and 
untreated groups. Cultures were plated on defibrinated horse blood agar 
and incubated for 24 hours. They were then examined for hemolytic 
streptococcus. Colonies of this organism were then picked, isolated in 
pure culture, and mailed to the Naval Medical School for grouping and 
typing. Only about 50 percent of the group A strains were typable. 
No type became predominant. The more common types were 5, 12 and 
3. The results of the throat culture studies are summarized in tables 25 
and 26. 


72 


Table 25. — Streptococcus typing according to diagnosis 
1 December 19^3 to 28 March 19J^Ji. 


Disease 

Cat. fever 

Tonsillitis 

Pharyngitis 

Scarlatina 

Other R. I. 


Serologic type 

C 

No. 

P 

No. 

C 

No. 

P 

No. 

C 

No. 

P 

No. 

C 

No. 

P 

No. 

C 

No. 

P 

No. 

Total 

1. 



1 








1 

2. 

1 




1 






2 

3. 

3 

2 

3 

1 

3 






12 

K 

9 


4 


2 






15 


3 


2 


4 






9 

9 

1 










1 

n_ 





1 






1 

12__ 

5 

3 

2 






3 


13 

14__ 

1 


1 


1 






3 


3 

1 

1 


2 


1 




8 

18_ 



2 








2 

19... 




1 

1 

1 





3 

26_ 

2 










2 

28_ 



1 








1 

30_ 

1 




1 






2 

32__ 

2 










2 

Sfi 

1 










1 

.89 



1 








1 

41... 

1 



1 





1 


3 

43.. 





1 






1 

44 . 

1 










1 

? 

21 

5 

17 

1 

13 

3 

2 


2 

1 

65 

Total_ 

55 

11 

35 

4 

30 

4 

3 

— 

6 

1 

149 


C = Control (Areas C and D). 

P = Areas on prophylaxis (E, F and G). 


Sulfadiazine Blood Level Determinations .—small percentage of pa¬ 
tients taking sulfadiazine prophylaxis are known to contract streptococcal 
infections. One possible explanation for this is an inadequate blood level. 
To collect information on this point, blood levels were determined for 
patients who contracted streptococcal disease in the groups on the pro¬ 
gram. The results are summarized in table 27. It is seen in this table 
that more than half of this group had blood levels of less than 1 mg. 
percent. Only one of these patients had a blood level above 2 mg. per¬ 
cent ; it is believed that otitis media in this patient was a mixed infection. 
The observations at this station indicated that a blood level of 2 mg. 
percent is desirable for protection against hemolytic streptococcal 
infections. 

Results 

Controlled Observations .—Careful clinical records of all respiratory 
and associated diseases were begun 10 days prior to the initiation of this 
program. Members of the Epidemiology Unit checked all diagnoses in the 
three groups on a sulfadiazine program and in the two untreated control 

73 




































































































Table 26 _ Streptococcal typings according to areas 

1 December 1943 to 28 February 1944 



groups. Illnesses have been separated into: (1) those admitted to the 
dispensary sickbays for respiratory diseases; (2) those admitted to the 
Naval hospital for more severe respiratory diseases; (3) those admitted 
with streptococcal infections; and (4) those admitted with other bac¬ 
terial infections. 

1. There is a significant difiference in the rates of these diseases be¬ 
tween the groups receiving prophylaxis and the control groups. The 
relative incidence of infections is shown in chart 23. 

2. The difference between treated and untreated groups is even more 
striking in the incidence of patients admitted to the hospital. This is 
shown in chart 24. 

3. Diseases in this category include scarlet fever; septic sore throat; 
tonsillitis, acute; pharyngitis, acute; otitis media, acute; and mastoiditis, 
acute. The significant difference between treated and untreated groups 
is shown in chart 25. 

4. Diseases in this category include meningitis, pneumonia (lobar and 
bronchopneumonia), laryngitis, and sinusitis. Most of these infections 
are believed to be bacterial diseases other than streptococcal. The sig¬ 
nificant difference in incidence between treated and control groups is 
shown in chart 26. 


74 
























































CHART 23 



Uncontrolled Observations .—In March 1944 all station personnel were 
placed on a daily dose of 1 gm. of sulfadiazine. Although the effect of 
this mass prophylaxis cannot be accurately evaluated, it was obvious to 
all medical and line officers that the program was highly effective. Be¬ 
tween 15 March and 15 April a high incidence of bacterial infections of 
the respiratory tract was to be expected at this station; instead, the inci¬ 
dence of streptococcal infections was minimal. A comparison of the mor¬ 
bidity rates of four respiratory diseases between 1944 and 1943 is pre¬ 
sented in table 28. 

Table 28 shows that meningococcal infections were eliminated during 
the over-all prophylactic program; scarlet fever was reduced to a mini¬ 
mum ; the pneumonia rate was slightly lower in 1944; catarrhal fever, 
which includes virus and bacterial infections, was also somewhat lower 
in 1944 than in 1943. 

Rheumatic Fever .—One of the purposes of this program was to reduce 
the incidence of rheumatic fever by preventing hemolytic streptococcal 
nificant difference in incidence between treated and control groups is 
months. Only three cases of rheumatic fever occurred. All these were 
in the control group. In March and April 1944, when the entire station 
received sulfadiazine prophylaxis, there were no cases of rheumatic fever. 
During the same period of 1943 there were 7.5 new cases each month. 

In brief, the incidence of rheumatic fever among trainees receiving 
sulfadiazine prophylaxis between December 1943 and April 1944 was 
zero. To achieve this, the incidence of streptococcal infections had to 

75 


























































CHART 24 



CHART 25 



76 













































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































CHART 26 



Table 27. —Analysis of streptococcal 


Unit 

Date 

Case 

no. 

Duration on sulfa¬ 
diazine 

E 

12/ 1/43 

2 

1 day. 

E 

12/14/43 

10 

13 days. 

E 

12/21/43 

X 

? . 

E 

12/30/43 

1 

0. 

F 

12/ 1/43 

4 

1 day. 

F 

12/ 1/43 

8 

1 day.— 

F 

12/ 3/43 

13 

3 days. 

F 

12/ 3/43 

18 

3 days. 

F 

12/ 6/43 

8 

6 days. 

F 

12/30/43 

5 

3 days.— 

G 

12/ 5/43 

M-1 

4 days- 

G 

12/ 6/43 

10 

6 days.. 

G 

12/30/43 

6 

2 days.. 

E 

1 /10/44 

1 

21 days... 

E 

1 /I1/44 

1 

17 days.. 

E 

1 /26/44 

1 

21 days. 

F 

1 /13/44 

2 

4 weeks. 

F 

1 /14/44 

2 

7 days. 

F 

1 /16/44 

2 

6 weeks. 

F 

1 /17/44 

2 

25 days. 

F 

1 /23/44 

2 

17 days. 


disease in units receiving prophylaxis 


Type of 
hem. 
strep. 

Blood sulfa level 

Diagnosis 

12 

0.8 mg. % . 

Catarrhal fever. 

12 

1.8 mg. %. 

Do. 

19 

1.7 mg. %. 

Tonsillitis. 

41 

0.0. 

Do. 

3 

1.4 mg. %. 

Do. 

19 

1.7 mg. . 

Pharyngitis. 

3 

Trace. 

Catarrhal fever. 

7 

Trac3. 

Do. 

3 

Trace. 

Do. 

? 

1.4 mg. % . 

Do. 

7 

Trace. 

Pharyngitis. 

? 

Trace. 

Do. 

7 

Trace. 

Tonsillitis. 

7 

1.5 mg. % . 

Pharyngitis. 

17 

0.3 mv. 

Catarrhal fever. 

7 

1 .f; Trip, % 

Do. 

7 

Trace. 

Do. 

12 

Tracp . _ 

Do. 

7 

2.7 mg. %. 

Acute otitis media. 

7 

Trace. 

Catarrhal fever. 

7 

Trace. 

Do. 


\ 


77 


















































































































































































































































































































Table 28. —Incidence of respiratory infections from H March 19AS to 
17 April 19AS compared to a similar period in 19AA 


Week ending 


Disease 

Mar. 

20 

1943 

Mar. 

18 

1944 

Mar. 

27 

1943 

Mar. 

25 

1944 

Apr. 

3 

1943 

Apr. 

1 

1944 

Apr. 

10 

1943 

Apr. 

8 

1944 

Apr. 

17 

1943 

Apr. 

15 

1944 


Rate* 

Rate* 

Rate* 

Rate* 

Rate* 

Rate* 

Rate* 

Rate* 

Rate* 

Rate* 

Ctaarrhal fever, acute. 

1,030 

707 

931 

738 

798 

726 

673 

617 

749 

683 

Meningococcal infections.. 

13.74 

0.0 

12.64 

0.0 

7.98 

0.0 

0.0 

0.0 

3.55 

0.0 

Pneumonia, lobar and 
broncho.. -. 

4.58 

12.5 

21.07 

2.80 

35.9 

0.0 

26.6 

27.4 

21.3 

19.1 

Scarlet fever.. 

68.6 

9.9 

122.2 

5.61 

123.7 

0.0 

125.4 

2.95 

209.7 

12.7 


* All rates per 100,000 per week. 

be reduced to a minimum. This was accomplished by sulfadiazine pro¬ 
phylaxis, but only by the daily administration of the drug to all hands. 


Untoward Sulfadiazine Reactions 

It was anticipated that untoward reactions to sulfadiazine would occur. 
The majority of these were minor and evanescent. The types of reac¬ 
tions encountered were similar to those which occur when sulfonamides 
are used therapeutically. Skin eruptions comprised the majority of all 
drug reactions. In a few instances, involvement of the mucous mem¬ 
branes, blood and blood-forming organs, and the genito-urinary system 
was observed. The time of onset of these reactions varied. Prompt 
anpphylactoid reactions were seen in a few recruits who had previously 
experienced untoward effects from sulfonamides administered thera- j 
peutically. Most dermal reactions occurred about the fourteenth day. ’ 
Reactions in those who had been taking the drug for approximately 21 
days were generally of a more serious nature. No attempt was made , 
to readminister the drug to those who developed manifestations of drug , 
sensitivity. These men were permanently removed from the prophylactic • 
program. Duplicate Excuse Forms were filled out by the medical of¬ 
ficer ; one copy was given to the company commander and the other placed 
in the files of the Epidemiology Unit for reference. Initially, intradermal 
sensitivity tests were made in all cases in which a dermal reaction devel¬ 
oped. This was done to ascertain whether or not recruits exhibiting 
dermal reactions had a dermal sensitivity to sulfonamides. The results 
revealed that these persons possessed no unusual dermal sensitivity that 
could be demonstrated by intradermal tests with sulfadiazine. 

Because no severe respiratory, streptococcal or meningococcal infec-j 
tions developed among the group who had been removed from the pro- J 
gram because of drug sensitivity, we are of the opinion that prophylaxis 
of more than 95 percent of a total recruit period is adequate to prevent 
infection among those in whom chemoprophylaxis has to be discontinued. 

78 
























Table 29. Analysis of drug reactions by number of days on sulfadiazine^ 
prophylaxis between December 19^3 and April 19UU 


Number of 
days 
on drug 

Average 

population 

Number of 
reactions 

Rate per 
thousand 

0-5 

61,196 

58 

.94 

6-10 

56,269 

417 

7.41 

11-15 

51,453 

500 

9.717 

16-20 

46,573 

198 

4.251 

21-25 

40,678 

154 

3.785 

26-30 

33,018 

84 

2.544 

31-35 

17,180 

25 

1.455 

36-40 

5,834 

8 

1.374 

41-45 

1,859 

5 

2.69 


Incidence Rates .—^All symptoms attributable to sulfadiazine are in¬ 
cluded in this analysis, and all these patients are classed as reactors, 
despite the fact that subsequent prophylactic doses may not have given 
rise to reactions. The over-all rate of reactions observed in this pro¬ 
gram was 2.28 percent. The incidence of reactions varied with the dura¬ 
tion of prophylaxis. An analysis of our observations is presented in 
table 29, grouped in 5-day periods. It is seen in this table that the 
highest incidence occurs between the eleventh and fifteenth day. This is 
graphically presented in chart 27. 

Types of Reactions .—^As previously mentioned, the types of drug reac¬ 
tions included the following main groups: (1) dermal; (2) mucous mem¬ 
brane; (3) hemopoietic, and (4) genito-urinary. 

Skin Reactions: Morbilliform rashes were present in more than 50 
percent of cases. This rash resembled the exanthemas of rubella and 
rubeola to a marked degree, at times making differential diagnosis diffi¬ 
cult. The absence of upper respiratory symptoms of a catarrhal nature, 
Koplik’s spots and enlarged postauricular nodes was often important 
in establishing a diagnosis of a skin eruption due to sulfadiazine. 

Scarlatiniform eruptions were the next most common form of dermal 
reactions observed in this series. These rashes varied from mild gener¬ 
alized erythemas to several degrees of punctiform eruptions. The ab¬ 
sence of accentuation of these lesions in the flexor surfaces of the axillae, 
antecubital fossae and groins, and throat cultures negative for beta hemo¬ 
lytic streptococci helped in establishing a diagnosis in questionable cases. 
Urticarial lesions occurred at any stage in the course of the prophylactic 
program. They were most frequently observed in those recruits who 
gave a history of previous untoward experience with therapeutic or pro¬ 
phylactic doses of sulfonamides. The lesions were characterized by 
wheals of various sizes and shapes, usually of a dusky color. They were 
found to occur most frequently on the torso. Purpuric lesions were noted 
in a small percentage of cases. These lesions appeared on the extrem- 

79 







CHART 27 


































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































ities, particularly the lower extremities and soles of the feet, involving 
fairly large areas of the affected parts. Circinoid or annular types of 
lesions occurred infrequently. Exfoliative dermatitis was observed in 
a few persons. 

Mucous Membrane: Erythema multiforme appeared in a number of 
instances. The lesions varied in type, size, and shape; they included 
macules, papules, and vesicles, frequently associated with mucous mem¬ 
brane lesions and fever. In a few instances, the eruption proceeded to 
the bullous state. These lesions varied in size, were fairly generalized, 
and involved mucocutaneous junctions, such as mouth, penis, and rectum. 
The areolae mammae were involved in a number of cases. Free sulfadia- 
zine was found in the fluid of these lesions several days after the last dose 
of sulfadiazine had been ingested. This type of eruption was associated 
with lesions of the mucous membrane, such as stomatitis and conjunc¬ 
tivitis. 

In addition, these patients exhibited generalized toxic symptoms with 
fever, loss of blood serum and proteins, and a tendency to an inversion 
of the albumin-globulin ratio. In all the severe cases and some of the 
moderately severe, mucous-membrane lesions occurred. Characteristi¬ 
cally, these usually occurred in men who had taken from 18 gm. to 21 
gm. of the drug. Of the mucous membrane lesions, conjunctivitis was 
the most frequent in occurrence. This was commonly associated with 
blepharitis. Conjunctivitis usually preceded more severe lesions of the 
erythema, multiforme complex: stomatitis, glossitis, cheilitis, exfoliative 
tracheobronchitis. Stomatitis and cheilitis responded slowly to treatment, 
and caused some difficulty in the administration of nourishment. A 
typical case history follows: 

Report of Cases 

An apprentice seaman, aged 25, white, had been on the prophylactic program 
for 15 days, so that he had taken a total of 15 gm. of sulfadiazine. Admitted 
to dispensary sickbay on 22 January 1944, complaining of a “cold” and “slight 
fever,” the patient was put to bed and given “2 pills.” 

Symptoms and Diagnosis. —Shortly after admission, he broke out in a rash accom¬ 
panied by pruritis which rapidly involved most of his body. On the morning 
of the twenty-third, he was seen by a medical officer of the epidemiology de¬ 
partment and a diagnosis of dermatitis medicamentosa due to sulfadiazine was 
made. Conjunctivitis was present at this time. 

Examinations of the Blood. —A sample of blood taken at this visit revealed a free 
sulfadiazine level of 2.0 mg. per hundred cubic centimenters of blood. The 
patient was transferred to the Naval hospital later in the day where another 
blood sample, taken approximately 12 hours later, showed a sulfadiazine level 
of 2.1 mg. per hundred cubic centimeters of blood. 

Symptoms on Hospital Admission. —On admission to the hospital the patient was 
found to be acutely ill with moderate respiratory distress and slight cyanosis 
of the face. His temperature was 102.2° F., pulse 132, and respirations 25. 


81 





Physical Observations. —Skin: The face was dusky and reddish, and showed 
cyanosis with diffuse vesicular rash and small bullae on the lips at the mucocu¬ 
taneous border. The neck had a vesicular type rash with large bullae on both 
sides. One of the blebs on the patient’s neck was needled and the fluid was 
aspirated. The free sulfadiazine level of this fluid was 1.4 mg. per hundred 
cubic centimeters. Vesicular and maculopapular lesions were present on the 
chest. The abdomen and extremities also had dusky, red maculopapular lesions. 

Eyes: Sclerae showed marked injection with dilation of small vessels. The 
lids showed pustular crusting, with conjunctivae injected. The pupils were 
equal and reacted to light and accommodation. 

Mouth: A friable, grayish membrane was present over the soft palate and 
tonsillar fossae. There were no bleeding points. The tongue was heavily 
coated. There were bullae just inside the lips and on the buccal mucosa. 

Ears: The ear drums were not seen. The external canals were involved 
with vesicular blebs, some of which were broken and discharged a serosan- 
guineous fluid. 

Lungs: Large rhonchi were heard throughout both lungs. No rales or 
bronchial breathing were heard. 

Abdomen: No masses were felt. 

Extremities: The extremities were normal except for skin lesions. 

Genitalia: Genitalia were normal. 

Reflexes: Reflexes were physiologically normal. 

Laboratory Findings. —The urine on admission was clear and had a specific gravity 
1.015; it was negative for albumin and sugar, and showed normal sediment. 
The sulfadiazine level was 0.9 mg. per hundred cubic centimeters. 

Blood Study. —The morning of the twenty-fourth, a complete blood study was 
done: The red blood count was 4,210,000; hemoglobin, 11 gm.; white blood 
count, 10,850; total protein 7.55 gm. per hundred cubic centimeters of serum; 
nonprotein nitrogen 41 mg.; blood urea nitrogen 18 mg. 

Treatment and Course. —At this time the chest showed many moist rales on both 
sides. The patient was given 1000 cc. of 5-percent dextrose in saline solution 
and a transfusion of 500 cc. of citrated blood. On this day the temperature 
was elevated to 105.5° F., and the patient looked worse. On the twenty-fifth 
the total protein had dropped to 5.4 gm. per hundred cubic centimeters; non¬ 
protein nitrogen was 30, and urea nitrogen, 15. Penicillin was instituted at this 
time, 20,000 units were given every 4 hours, and the diagnosis was changed to 
bronchopneumonia. On the twenty-seventh the general condition was about the 
same; total proteins were 6.25; albumin was 3.95, and globulin 2.30. Another 
transfusion was given of 500 cc. of citrated blood, and periodic aspiration of 
mouth and pharnyx with a suction apparatus was begun. Because of his 
increased respiratory difficulty the patient was placed in an oxygen tent. On 
the twenty-ninth the total protein was down to 5.62 gm., albumin, 2.62, and 
globulin, 3.00. Nonprotein nitrogen was 29 mg. per hundred cubic centimeters. 

The patient continued to have a stormy, febrile course, the temperature 
ranging between 101° F. and 103° F.'for 21 days. He was in the oxygen tent 
the greater part of this time. 

On 9 February 1944 a roentgenogram of the chest was taken. The report 
read: “There is a widespread, disseminated, exfoliative and exudative bron¬ 
chitis in both lungs, more concentrated in the right base posteriorly.” Skin 
lesions healed slowly and the conjunctivae cleared; however, the blepharitis 
persisted and stringy adhesions were developed at the outer canthi of both eyes. 

On 8 March 1944 a follow-up roentgenogram revealed that: “The process 
in the right base has improved considerably, but resolution is not complete.” 

82 




On 13 March 1944 the total protein was 6.72 gm. per hundred cubic centi- 
^ meters. By this time the skin lesions had all healed without scarring, but they 
* left some slight purplish discoloration. 

Effects on Blood and Blood-Forming Organs: Over a 3-month period 
a number of patients with mild morbilliform skin reactions were admitted 
to one sickbay for a diagnostic record. Blood studies were made of 72 of 
these patients. The average erythrocyte count was 4,475,000 with a 
range of 3,600,000 to 5,400,000. The average white count was 7,034 
with a range from 2,100 to 13,000. Sixteen or 22.2 percent of these 
patients had a white count of less than 5,000, a range from 2,100 to 4,990, 
and an average of 4,036. These patients had been taking the drug an 
average of 11.4 days. One patient developed a severe neutropenia. He 
had received 1 gm. of sulfadiazine daily for 33 days. His history follows: 

The patient was admitted to the sickbay on 10 January 1944 because of a 
generalized rash and pruritis. The only positive (findings on examination were 
a generalized morbilliform eruption and slight fever. On 11 January 1944 a 
blood count revealed that he had a secondary anemia and marked neutropenia. 
The red blood count was 3,850,000; hemoglobin 10.5 gm.; the white blood count 
2,800; and the differential count showed monocytes, 4 percent; lymphocytes, 
80 percent; granulocytes, 14 percent; and band forms, 2 percent. 

The patient was transferred to the hospital for further study and treatment. 
On 12 January 1944 the red blood count was 3,740,000; hemoglobin 10.5 gm. 
and white blood count 2,600, with a differential count of monocytes, 4 percent; 
lymphocytes, 85 percent; granulocytes, 9 percent; and band forms, 2 percent. 
A transfusion of 500 cc. of whole blood was given on this day. On 13 January 
I 1944 blood studies revealed a red blood count of 3,880,000; hemoglobin, 11 gm., 

1 white count, 4,800; monocytes, 2 percent; lymphocytes, 84 percent; granu¬ 
locytes, 13 percent; and band forms, 1 percent. On 14 January 1944 the red 
blood count was 4,210,000 and white count 5,900 with monocytes, 5 per cent; 
lymphocytes, 60 percent; granulocytes, 34 percent; and band forms, 1 percent. 

Subsequent daily blood studies revealed a rapid improvement in the blood 
picture, and on 21 January 1944 the red, white and differential counts were 
normal. The eruption cleared spontaneously within a few da 3 's following ad¬ 
mission, and the patient was entirely asymptomatic during his stay in the 
hospital. His response to the initial blood transfusion was so prompt that 
further transfusions or other treatments were not necessary. 

Effects on Genito-Urinary System: Urinary complications were vir¬ 
tually nonexistent during the entire course of the Streptococcal Control 
Program. It is only mentioned in this study to emphasize the fact that 
persons may be given small daily doses of sulfadiazine prophylactically 
over a long period of time without the danger of producing renal impair¬ 
ment of urinary tract complications. Although no special studies were 
made to ascertain what effects 1 gm. of sulfadiazine daily had on the 
urinary excretory system of the large group treated, urinalyses were made 
of all who reported to the dispensaries with other toxic manifestations 
and of those hospitalized for various other reasons not associated with the 
antistreptococcal program. This afforded a means of carefully sampling 

83 

A 

'i 

iS) 



two large groups who had been receiving 1 gm. of sulfadiazine daily. In 
these two groups there were no cases in which there was any evidence of 
renal or urinary tract involvement. 


Estimate of Number of Man-Days Saved by Streptococcal Control 
Progrom from 1 December 1943 to 1 March 1944 

In order to ascertain the number of man-days saved by the Strepto¬ 
coccal Control Program, the number of sick days lost by each person ad¬ 
mitted with a respiratory infection was obtained. This was done for a 
3-month period, from 1 December 1943 to 1 March 1944, when only three 
recruit areas received prophylaxis and when there was a suitable control 
group available. The number of sick days for each person in the control 
and treated areas was obtained from the F card of each patient. 
The diseases considered were catarrhal fever, acute; pharyngitis, acute; 
scarlet fever; bronchitis, acute; tracheitis, acute; tracheobronchitis, acute; 
rhinitis, acute; sinusitis, acute; otitis media, acute; mastoiditis, acute; 
bronchopneumonia and lobar pneumonia; cerebrospinal fever, meningo- 
coccic; and rheumatic fever. 

The only factor used was: 

Population of treated group 

Population of control group 

This was employed to correct for the divergence in populations which 
existed between the treated and control groups. Following this correc¬ 
tion, the number of sick days in the treated group was subtracted from 
the number of sick days in the control group, giving the number of man- 
days saved. These values were obtained and then totaled. A conserva¬ 
tive estimate of man-days saved during the controlled program is: De¬ 
cember: 11,382; January: 12,663; February: 7,924; total: 31,969. The 
extension of prophylaxis to the entire station on 1 March undoubtedly 
doubled the number of man-days saved during the controlled program. 


Summary and Conclusions 


1. Sulfadiazine (1 gm. daily) was administered prophylactically to 
63,392 Naval personnel from 1 December 1943 to 1 April 1944. 

2. The incidence and rates of all types of bacterial respiratory tract dis¬ 
eases, particularly streptococcal infections, was significantly reduced. 

3. Blood levels of 2.0 mg. percent appeared satisfactory for the pre¬ 
vention of most streptococcal diseases. 


4. Rheumatic fever and meningococcus meningitis were 
in recruits receiving sulfadiazine prophylaxis. 


nonexistent 


84 




5. Evanescent phenomena attributable to sulfonamide idiosyncrasy oc¬ 
curred in 2.28 percent. Several severe sulfadiazine reactions occurred, 
but there were no deaths. Careful observation of all recruits on a pro¬ 
phylactic program is essential to prevent fatal reactions. 

6. Over 30,000 man-days were saved in the first 3 months of the con¬ 
trolled program. 

7. The institution of the prophylactic sulfadiazine program marks a 
significant advance in the mass prevention of bacterial infections of the 
respiratory tract, particularly those caused by hemolytic streptococcus. 


85 







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Report 5 


Streptococcus Prophylaxis Program 

U. S. Naval Training Center, Bainbridge, Md. 

From Epidemiology Unit 67^^ 


I program for the control of streptococcal infections by the use of pro- 
1 phylactic doses of sulfadiazine was instituted at Bainbridge Naval Train- 
i ing Center in December 1943. This program was planned so that facts 
I on the relative effectiveness of several dosages of sulfadiazine and different 
ways of administration might be compared and evaluated. The follow¬ 
ing questions were posed: What protection against streptococcal in¬ 
fections can be expected from the ingestion of sulfadiazine, 1 gm. daily? 
; Is the administration of the drug on alternate weeks as effective as con¬ 
tinuous prophylaxis? Is the dosage of 0.5 gm. of sulfadiazine daily as 
effective as 1 gm. daily? The purpose of this report is to present the 
results of the Streptococcal Control Program as conducted at Bainbridge 
between 13 December 1943 and 2 April 1944. 

Functions of Epidemiology Unit 67 

The administration of this program was the responsibility of Epidem¬ 
iology Unit 67 which consisted of four medical officers, five pharmacist 
! mates and a wave yeoman. The program was conducted under the 
supervision of the Senior Medical Officer of the station. Line officers 
were advised regarding the administration of sulfadiazine. Respiratory 
illnesses were ..checked by clinical and bacteriologic examinations. Rou¬ 
tine diagnostic procedures were handled in the Unit’s laboratory. Throat 
cultures were plated on horse blood agar; colonies of hemolytic strepto- 

* Participants: Milton J. H. Grand, Lieutenant Commander (MC) USNR; 
John B. Stanbury, Lieutenant Commander (MC) USNR; Ernest W. Eker- 
MEYER, Lieutenant (MC) USNR. 

Assistants: John Emmett Peters, PhMlc; James Vincent Dattilo, PhM2c; 
William Robert Overs, PhM2c; Robert Samuel Stone, PhM2c; Dean, Graeme 
Jones, PhM2c. 


87 





coccus were isolated in pure culture; these organisms were then trans¬ 
ferred to the National Naval Medical Center for serologic grouping and 
typing. 

Organization of Five Groups of Personnel 

Five groups of enlisted men were given sulfadiazine prophylaxis: (1) 
The Naval Academy Preparatory School (naps), consisting of about 600 
men; (2) Regiment 1, a Service School group of about 5,000 men; (3) 
Regiment 2, a ‘‘boot” camp, consisting about 3,000 Negro trainees ; (4) 
Regiment 3, a “boot” camp of about 5,000 white trainees; (5) Regiment 
4, a “boot” camp of about 5,000 white men, similar to Regiment 3. 

The NAPS complement remained unchanged throughout the period of 
observation. The Service School personnel (Regiment 1) were at Bain- 
bridge from 6 weeks to 4 months. Recruit training lasted from 6 to 8 
weeks. New recruits were admitted to Regiments 2, 3, and 4 several 
times each week. These regiments were maintained at full strength and 
the turnover was rapid. Each of the five groups had its individual sulfa¬ 
diazine dosage and schedule for administration. 

Administration of Sulfadiazine Prophylaxis 

Two different methods were required for the dissemination of the sul¬ 
fadiazine tablets: one for the recruits and one for the Service School 
personnel. 

Recruits (Regiments 2, 3 and 4).—^All recruits entering the station 
passed through the same receiving unit where they were formed into com¬ 
panies of approximately 135 men each. While in this unit, the men were 
housed and messed together. After 2 or 3 days, the recruits were placed 
in a company and billeted in permanent barracks. The sulfadiazine tab¬ 
lets and muster sheets were distributed to the commanders of the com¬ 
panies who' were instructed to check the name of each man when the 
tablets were taken by him. At the end of each week the company com¬ 
mander returned the checked-off muster sheets and a new supply of sulfa¬ 
diazine was issued him with another muster sheet. The company com¬ 
manders were made responsible for the administration of the drug. They 
were informed of the importance of prophylaxis and the necessity for the 
strict adherence to the regularity of administration. 

Service Schools (Regiment 1).—Since all the Service Schools were 
divided into sections of approximately 50 men each, this unit was utilized 
for distributing the tablets. At the beginning of each week there was a 
meeting with the appointed leaders of all the sections and a muster sheet 
and a supply of the drug were given to them. These sheets showed the 
names of the men, their home states and ages, and had a place for a daily 
check-off of the days that they received the drug or a daily check-off of 


! 


88 





days under training if they were not receiving medication that week. 
These section leaders were instructed to give each man the prescribed 
number of tablets at 1930 each day and to observe the actual taking of the 
tablets. The muster sheets containing the data were collected at the end 
of each week and the number of days of medication in the treated group 
and the number of days of men under training in the untreated group 
were determined. 

Method of Collecting and Tabulating Data 

Each of the regiments was served by two dispensaries to which an 
assigned medical officer of the Epidemiology Unit made daily visits. 
From the log book in each dispensary he was informed of all patients 
with respiratory symptoms. He recorded the number of new respiratory 
sick calls for each company under separate headings. Each man ad- 
1 mitted to sickbay or hospital for a respiratory illness was examined by 
this medical officer; a throat culture was taken and a tentative diagnosis 
was made. These cases were followed and the diagnoses were reviewed 
in the light of the throat culture results and additional clinical observa¬ 
tions. These data were collected, summarized weekly, and disease rates 
compiled for each company in each of the study groups. 

We were particularly interested in the accurate differentiation of 
' streptococcal infections; therefore, if a patient appeared to have ton- 
; sillitis or pharyngitis but the throat culture was negative for hemolytic 
streptococci, the patient was given a diagnosis of “catarrhal fever, acute” 
i in our records. However, if the medical officer made an original diag- 
! nosis of “catarrhal fever, acute” and had a subsequent throat culture of 
hemolytic streptococci, the diagnosis was not changed and the patient 
was considered to be a carrier. The number of such cases, however, was 
small. An occasional patient with tonsillitis, pharyngitis, or scarlet fever 
was found among the treated group who, through neglect or indifference, 
had not taken his medication according to schedule. Any man who had 
failed to take sulfadiazine was eliminated from the series. Here, too, the 
number of such persons was small. In every instance in which a strepto¬ 
coccal infection occurred in a treated group the patient was questioned 
in detail about his adherence to his prescribed schedule of drug admin¬ 
istration and this information was checked with the muster sheets pre¬ 
viously turned in by the section leaders. 

The incidence of streptococcal disease was calculated in two ways: 
One of these consisted of determining the cases of scarlet fever, tonsillitis, 
and pharyngitis confirmed by throat cultures. The second method con¬ 
sisted of classifying all cases of respiratory infection with hemolytic 
streptococci in the flora as probable streptococcal infections. 


89 




Results of Sulfadiazine Prophylaxis 

NAPS .—The purpose of the control program in this group was to 
protect all hands against streptococcal infections. The group consisted 
of 634 men who matriculated in October 1943 and engaged in training 
until June 1944. All hands were given 1 gm. of sulfadiazine daily. Their 
state of health was observed carefully and throat culture studies were 
made every 3 weeks of the entire student body. The results of this con¬ 
trol program are presented in tables 30 and 31. 

Table 30 shows that all but four persons escaped frank streptococcal 
infections and that in all the respiratory infections except five, hemolytic 
streptococcus was excluded as the causative agent. 

Table 31 shows that hemolytic streptococcus type 1 was carried by 
members of this group prior to the institution of the program; that it 
persisted throughout the winter months, but that its prevalence did not 
increase. Two men acquired type 36 in the throat flora. Type 19 was 
strikingly predominant at Bainbridge. It manifested extreme communi¬ 
cability and invasiveness, and can be classified as the epidemic type 
throughout the period of observation; it was, however, implanted in only 
two members of this group. 

Regiment 2 .—The purpose of the program in this group was to deter¬ 
mine the effectiveness of a daily dosage of 0.5 gm. sulfadiazine in pre¬ 
venting streptococcal infections. This regiment consisted of about 3,000 
Negro recruits. It was divided into two equal parts: One, designated 
as Group B, consisted of the odd-numbered companies. Group B re¬ 
ceived 0.5 gm. of sulfadiazine daily and Group A served as an untreated 
control through 3 periods (4 weeks each) of observation. The entire 
company was given sulfadiazine, 1 gm. daily, during a fourth period of 
4 weeks. The results of this program are shown in chart 28 and tables 
32 and 33. 

Chart 28 indicates the effectiveness of a daily prophylactic dose of 0.5 • 
gm. of sulfadiazine and perhaps a greater effectiveness of a daily dose 
of 1 gm. of sulfadiazine. The incidence of sick calls for respiratory, 
symptoms in the untreated group was twice that of the treated group and 
the incidence of respiratory diseases requiring bed care in the untreated 
group was about 3 times that of the treated group. In both sick calls 
and admissions the difference in incidence between the untreated and 
treated groups is statistically significant. 

Table 32 shows that in the untreated group the incidence of respiratory 
infections which were probably caused by hemolytic streptococcus was 11 
times that of the treated group. The incidence of frank streptococcal 
diseases in the untreated group was 24 times that of the treated group. 

90 . 


Table 30. —Incidence of respiratory infections: Naval Academy 

Preparatory School 


Four- 

week 

period 

ending 

Popu¬ 

lation 

Sick call 

Dispensary and 
hospital admis¬ 
sions for R. I. 

Respiratory ad¬ 
missions with 
positive throat 
cultures 

Tonsillitis, pharyn¬ 
gitis confirmed by 
throat culture 

No. of 

cases 

Rate/ 

1,000 

No of 

cases 

Rate/ 

1,000 

No. of 

cases 

Rate/ 

1,000 

No. of 

cases 

Rate/ 

1,000 

1/9/44 

467.4 

66 

141.2 

2 

4.28 

0.0 

0.0 

0.0 

0.0 

2/6/44 

576.2 

98 

170.1 

7 

12.15 

0.0 

0.0 

0.0 

0.0 

3/5/44 

541.1 

84 

155.2 

10 

18.48 

2 

3.68 

2 

3.68 

4/2/44 

483.8 

56 

115.8 

7 

14.47 

3 

6.20 

2 

4.13 


Table 31. —Serologic types of hemolytic streptococcus in 
throat flora of *^naps** 


Type 

11/18/43 

12/21/43 

12/29/33 

1/10/44 

2/1/44 

1 

1 




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29 . 


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1 



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5 





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2 

41 


1 




A-Not Typable... 

3 

1 

2 

6 

15 

Total. 

28 

3 

5 

22 

33 

Total cultures.-. 

577 

344 

294 

400 

560 

Carrier rate.. 

4.85 

0.95 

1.70 

5.50 

5.79 


91 







































































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93 














































Table 32. —Incidence of respiratory infections {probably hemolytic 
streptococcal) in regiment 2 


Four- 

week 

period 

ending 

Population average 
strength 

All respiratory illness with positive hemo¬ 
lytic streptococcus 

x/<r 

P 

A— 

control 

B— 

treated 

A—control 

B—treated 

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cases 

Rate/ 

1,000 

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cases 

Rate/ 

1,000 

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1706.4 

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46.88 

9 

5.27 

7.43 

<0.0001 

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1488 3 

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79.02 

9 

6.05 

9.60 

<0.0001 

4/2/44 


2613.6 



18 

6.88 











In summary, it appears that sulfadiazine prophylaxis, 0.5 gm. daily, 
reduced the incidence of respiratory diseases, reduced the incidence of 
respiratory infections probably caused by hemolytic streptococcus, and 
almost eliminated frank hemolytic streptococcal disease in these Negro 
recruits. 

Regiment 4 .—The purpose of the streptococcal control program in 
this regiment was to determine the comparative effectiveness of con¬ 
tinuous prophylaxis to prophylaxis on alternate weeks. A daily dosage 
of 1 gm. of sulfadiazine was used. The regiment was divided into three 
groups by random selection. Each had an average population of about 
1,500 men and this strength was maintained by the addition of new com¬ 
panies of recruits assigned to each group in rotation. The companies 
of all three groups intermingled in the barracks. Group A received no 
prophylaxis and served as a control; Group B received sulfadiazine, 1 
gm. daily in alternate weeks; Group C received a continuous daily dose 
of 1 gm. The results of this program are shown in chart 29 and table 
34. 


Table 33. —Incidence of frank streptococcal infections in regiment 2 


Four- 

week 

period 

ending 

Population average 
strength 

Confirmed 

Scarlet Fever, Tonsillitis and 
Pharyngitis 

x/<r 

P 

A— 

control 

B— 

treated 

A—control 

B—treated 

No. of 

cases 

Rate/ 

1000 

No. of 

cases 

Rate/ 

1000 

2/6/44 

1642.2 

1706.4 

26 

15.83 

2 

1.17 

4.56 

<0.0001 

3/5/44 

1430.1 

1488.3 

64 

44.75 

2 

1.34 

7.66 

<0.0001 

4/2/44 


2613.6 



3 

1.15 













94 








































UNTRCATCO CONTROL. 

I GRAM daily alternate WEEKS. 
I GRAM DAILY CONTINUOUSLY. 


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Chart 29 shows the relative incidence of sick calls and admissions for 
respiratory infections in the three groups. The sick call rate for respir¬ 
atory symptoms and the admission rate for respiratory diseases show a 
significant difference in favor of both treated groups, but only in the 
second 4-week period, was the continuously-treated group significantly 
better than the alternate-week group. The administration of sulfadia¬ 
zine, 1 gm. daily, to all hands in March was accompanied by a fall in the 
incidence of respiratory symptoms and diseases. 

Table 34 shows a striking difference between the control group and 
the treated groups. The group taking continuous prophylaxis had a 
significantly lower incidence of presumptive and proved streptococcal 
infections than the group receiving sulfadiazine prophylaxis in alternate 
weeks. 

In summary, it was observed that continuous prophylaxis of 1 gm. of 
sulfadiazine daily was more effective; was easier to control, and caused 
no more untoward reactions than the administration of the drug in alter¬ 
nate weeks. The institution of continuous dosage of 1 gm. daily to all 
hands at a time when the activity of respiratory pathogens was increasing, 
was followed by a marked reduction in respiratory symptoms, in admis¬ 
sions for respiratory diseases, and especially in the incidence of strepto¬ 
coccal infections. 

Regiment 1 .—The purpose of the control program in this regiment 
was also to determine the relative effectiveness of continuous prophy¬ 
laxis with alternate weeks of prophylaxis, using a daily dose of 0.5 gm. 
of sulfadiazine. This regiment, consisting of about 5,000 Service School 
personnel, was divided into three groups by random selection. Group 
A was untreated; Group B received 0.5 gm. sulfadiazine daily in alter¬ 
nate weeks; Group C received 0.5 gm. daily. (During the first 4-week 
period Group C received 1 gm. of sulfadiazine daily in alternate weeks 
instead of 0.5 gm. daily.) After 12 weeks the entire regiment was placed 
on a dose of 1 gm. administered daily. The results of this program 
are shown in chart 30 and table 35. 

Chart 30 shows the incidence of sick calls and admissions for respir¬ 
atory infections in the three groups. The difference in respiratory in¬ 
fection rates between the control and treated groups is statistically sig¬ 
nificant. The lowest rates occurred in the group on a program of con¬ 
tinuous prophylaxis. The administration of sulfadiazine, 1 gm. daily, 
to all hands in March was accompanied by a fall in the incidence of 
respiratory symptoms and disease. 

Table 35 shows the incidence of presumptive and frank streptococcal 
infections. The difference in streptococcal infection rates between the 
controls and groups treated with 0.5 gm. of sulfadiazine is statistically 
significant. The incidence of streptococcal infections in the group re¬ 
ceiving continuous prophylaxis was slightly lower than in the group 

97 




Table 35 .—Incidence of respiratory infections {probably hemolytic streptococcal) 

and frank streptococcal diseases in regiment 1 



/ 


98 























































taking the drug in alternate weeks. The institution of a continuous 
daily dose of 1 gm. in March was followed by a striking reduction in the 
incidence of these infections. 

In summary, it was observed that a prophylactic dose of sulfadiazine, 
0.5 gm. daily, was effective; continuous dosage appeared to be preferable 
to the administration of the drug in alternate weeks. Increasing the 
daily dose of sulfadiazine from 0.5 gm. tO' 1 gm. on 5 March 1944 when 
the incidence of streptococcal infections was rising throughout the un¬ 
treated groups was followed by a further marked reduction in the rate 
of presumptive and frank streptococcal infections. 

Regiment 3 .—This regiment of about 5,000 trainees received no pro¬ 
phylaxis until 25 February. Between 13 December 1943 and 25 Feb¬ 
ruary 1944 there were 95 cases of frank scarlet fever. The causative 
agent was serologically identified in the majority of cases as hemolytic 
streptococcus type 19. During February the incidence of scarlet fever 
rose sharply. Concomitant with this there was a sharp rise in the rate 
of other streptococcal respiratory infections. It was therefore believed 
necessary to check this sudden development by instituting a sulfadiazine 
program. On 25 February 1944 half of the regiment was placed on a 
sulfadiazine program of 1 gm. daily. The results of treating half of this 
regiment during a severe streptococcal outbreak are shown in charts 31 
and 32. 

Chart 31 shows the effect of sulfadiazine prophylaxis on the sick call 
and admission rates for respiratory infections. Chart 32 shows the ef¬ 
fect of sulfadiazine on the scarlet fever rate. Except for the first week 
of the program, during which the treated received only three doses of 
sulfadiazine, there was a statistically significant difference between 
treated and untreated groups in the rates of respiratory infections and 
scarlet fever. 

Serologic Types of Hemolytic Streptococcus Prevalent at Bainbridge 

All strains of hemolytic streptococcus recovered from those on the 
prophylactic program and appropriate samples of strains from infected 
persons in the control groups were shipped to the National Naval Med¬ 
ical Center for typing. The types recovered from patients with respir¬ 
atory infections are presented in tables 36 and 37. Type 19 was the 
prevalent type at Bainbridge throughout this period of observation. 

Untoward Reactions 

More than 36,000 men received sulfadiazine prophylaxis during this 
4-month period. The duration of prophylaxis varied from 4 weeks in 
recruits to 4 months in the '‘naps.” Altogether 85 men developed 
symptoms referable to sulfadiazine. These were classified as follows; 
Urticarial rash, 27; morbilliform rash, 20; scarlatiniform rash, 18; other 


99 


100 “1 A * UNTREATED CONTROL. 


CHART 31 



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E 

3 


o 

Eh 


102 


























































































































Table 37 .—Serologic types of hemolytic streptococcus in different regiments 


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103 





























































































































dermal lesions, 12; exfoliative dermatitis, 3; stomatitis, 4; questionable 
circulatory collapse, 1. Of these 28 were retested and 19 of the 28 were 
able to resume the drug. The relation of drug reaction to dosage is 
shown in table 38 and 39. It is seen that the schedule of drug admin¬ 
istration had little effect on the rate of dermal reactions. Untoward 
symptoms in most developed in the second or third week when from 7 
gm. to 20 gm. of the drug had been ingested. Five patients developed 
reactions during the first days of prophylaxis. 

There were altogether five severe dermal reactions. Two patients 
became critically ill. There was one death which proved at autopsy to 
be associated with leukemia. 

Report of Cases 

Case 1 .—A second class seaman, aged 25, was admitted to the station dispensary 
because of a rash, vomiting, and blisters in his mouth. He had been taking 
0.5 gm. of sulfadiazine daily for 2 weeks. He gave a history of sensitivity to 
wool. He had recently arrived from his “boot” training elsewhere where sev¬ 
eral cases of bullous stomatitis had occurred. 

Examination on entry showed a temperature of 102° F.; edema of the face 
and hands; a few blister-like lesions in the mouth, measuring about 4 mm. 
in diameter, and a discrete macular, erythematous rash on the chest, abdomen, 
and extremities. Fine vesicles were seen in the centers of some of these lesions. 

Urinalysis on admission was normal and showed a few sulfonamide crystals 
in the sediment. 

The red blood count was 4.84 million with 92 per cent hemoglobin; the white 
count was 20,050 with 75 percent neutrophils. 

For the next 10 days the patient’s temperature was elevated to 102° F. The 
oral lesions sloughed, ulcerated, and made eating and drinking extremely dif¬ 
ficult. The cutaneous lesions rapidly subsided. On the twenty-second hos¬ 
pital day the patient developed right lobar pneumonia which was treated with 
250,000 Oxford units of penicillin. The patient was discharged essentially well 
on the forty-second hospital day. 

Case 2 .—An 18-year old colored steward’s mate was admitted to the dispensary 
and transferred to the hospital because of a rash and symptoms of a respiratory 
infection. He had been receiving prophylactic sulfadiazine, 1 gm. daily, for 
14 days. A diagnosis of German measles was made. On arrival at the hos¬ 
pital, signs suggestive of pneumonia were found, but his general condition 
became progressively worse. He developed a brawny edema of the face, chest, 
and arms, and some scaling of the skin. Clinical evidence of pulmonary dis¬ 
ease increased through the course of his illness. His temperature ranged from 
101° F. to 104° F. Blood and urine showed no noteworthy abnormalities. 
Throat culture was negative for hemolytic streptococci and two blood cul¬ 
tures were negative. 

Treatment and Course: The patient was treated with large doses of peni¬ 
cillin for pneumonia. He was placed in an oxygen tent on the tenth day, but 
this did not improve his condition and he died on the eleventh day. 

Autopsy: Postmortem examination revealed gross evidence of bilateral 
bronchopneumonia, a liver weighing just over 2,000 gm. which, on cut surface, 
was somewhat pale. The spleen weighed slightly over 600 gm., was deeply 
colored, friable, and showed several healed infarcts. The right kidney showed 

104 


Table 38. —Sulfonamide reactions in relation to drug schedule 


Method of administration 

0.5 gm. 
alternate 

weeks 

0.5 gm. 
continu¬ 
ously 

1 gm. 
alternate 
weeks 

1 gm. con¬ 
tinu¬ 
ously 

Number of men. 

4,470 

3.57 

4,414 

2.26 

6,160 

21,051 

Rate per 1,000 of dermal reactions. 

2.92 

4.18 




Table 39. — Sulfonamide reactions in relation to total drug ingested 


Grams of sulfadia¬ 
zine 

Number 

cases 

Grams of sulfadia¬ 
zine 

Number 

cases 

1. 

5 

11-15. 

42 

2 ... 

3 

16-20. 

27 

3 .. 


21-25. 

13 

4 . 

1 

21-25. 

8 

5. 

0 

Over 30. 

5 

6-10 ... 

27 




evidence of an old healed pyelonephritis. There was a megalo-ureter on that 
side. The other kidney was -slightly larger than normal. There was gener¬ 
alized lymphadenopathy. On microscopic examination this proved to be 
leukemia. 

Comparative Prophylactic Effects of 1 Gm. and 0.5 Gm. of Sulfadiazine 
Administered Daily 

The relative effectiveness of these two doses was tested in Regiments 
1 and 2. In each of these regiments the group receiving a daily dose 
of 0.5 gm. of sulfadiazine in February was given a 1 gm. dose in March. 
In Regiment 2 with a low rate of respiratory disease the increased dosage 
had little or no effect. In Regiment 1 with a moderate rate of respiratory 
infections there was a striking improvement following the increase in 
dosage from 0.5 gm. to 1 gm. The sick calls rate fell from 73 to 63; 
the hospital admission rate from 22 to 7; the incidence of probable strepto¬ 
coccal infections from 11 to 4; the incidence of frank streptococcal infec¬ 
tions from 6 to 2. These changes occurred during March at a time when 
the incidence of streptococcal disease was rising in the untreated group 
of personnel. It appeared that a daily dose of 1 gm. of sulfadiazine was 
more effective than 0.5 gm. in Regiment 1. 

Comments 

1. Will sulfadiazine prophylaxis create drug-fast strains of hemolytic 
streptococcus? The clinical observations made at Bainbridge suggest 
that none of the sulfadiazine schedules in this prophylactic program 
created drug-fast strains. 


105 

































2. Will sensitization result from the use of alternate weeks of prophy¬ 
laxis? A small percentage manifested a drug idiosyncrasy; however, 
prophylaxis did not appear to sensitize these recruits. 

3. If the institution of prophylaxis prevents respiratory infections, will 
this affect the respiratory rate in the untreated companies of the regi¬ 
ment? It was observed that the untreated companies of the regiments 
engaged in the prophylactic program escaped a severe streptococcal out¬ 
break, such as occurred in the untreated regiment. Whether this was 
due to a reduction in the number of susceptibles in the regiment is 
unkown. 

Summary 

1. Sulfadiazine prophylaxis was administered to five regiments at the 
Bainbridge Naval Training Center. 

2. Several drug dosages and schedules were tested to determine the 
most effective and simplest standard for mass prophylaxis. 

3. Continuous daily dose of 0.5 gm. of sulfadiazine was found simple 
to administer and effective in preventing respiratory diseases. 

4. The rates of bacterial infections of the respiratory tract in recruits 
receiving this dosage were significantly less than in the untreated controls. 

5. The institution of a station-wide sulfadiazine prophylactic program 
of 1 gm. daily on 1 March 1944 was followed by a striking drop in 
respiratory disease rates. 

6. It appeared that a daily sulfadiazine dose of 1 gm. was somewhat 
more effective than 0.5 gm. 

7. A daily dose of 1 gm. sulfadiazine appeared highly effective in: 
(a) checking a scarlet fever outbreak; (b) significantly reducing the 
incidence of streptococcal infections throughout the station; and (c) pre¬ 
venting the implantation of hemolytic streptococcus in the throat flora of 
600 men attending the Naval Academy Preparatory School throughout 
the winter and spring months. 


106 


Report 6 

The Streptococcal Control Program 

U. S. Naval Construction Center, Davlsville, R. I. 

From Epidemiology Unit 42^ 


Sulfadiazine prophylaxis was instituted at the U. S. Naval Construction 
Center, Davisville, Rhode Island on 15 November 1943. The objectives 
of the program were to control streptococcal infections, determine the 
effectiveness of sulfadiazine prophylaxis, and assess the relative value of 
several doses and schedules of administration. The present report is a 
summary of our observations made between November 1943 and March 
1944. 

Administration of Sulfadiazine 

Alternate battalions were designated on arrival on the station either as 
a treated or a control group. The method found most satisfactory for 
the dispensing of tablets was to have the company commander (Chief 
Petty Officer) obtain a supply of tablets from the battalion sickbay and 
dispense the tablets at morning muster, using a check-off list. 

The chiefs were instructed to witness the ingestion of the drug; never¬ 
theless, a certain number failed to swallow the drug. In order to obtain 
the cooperation of the men, various methods were used to explain the 
purpose of the study. The battalion medical officer spoke to the men as 
a group, stressed the prophylactic value of the drug, and explained the 
possibility of reactions. The station paper (Bulldozer) published articles 
explaining the purpose, and later, published the results of the study. Suit¬ 
able posters in cartoon form were posted on bulletin boards, and the med¬ 
ical officer of the unit spoke to the hospital corpsmen regarding prophy- 


* Participants: W. A. Myers, Lieutenant Commander (MC) USNR; W. T. 
Kees, Lieutenant Commander (MC) USNR; Theodore Cohx, Lieutenant, (jg) 
H-V(S), USNR; W. E. Mosher, Jr., Lieutenant (MC) USNR; J. L. Garey, 
Lieutenant (MC) USNR. 


107 



laxis. The lifting of liberty cards of men who did not take their tablets 
was found to be a fairly effective method of checking delinquency in taking 
the drug. 

Several different methods of administration and dosages were used: 


Dose 

A. 1 gm. 

B. 1 gm. 

C. 1 gm. 

D. 0.5 gm. 


SULFADIAZINE TREATED GROUPS 

Administration 

.Daily 

.Every other day 

.Twice weekly 

.Daily 


Schedules other than daily proved unsatisfactory because of administra¬ 
tive difficulties, and they were therefore discontinued. 


Clinical Results 

This report can best be presented by dividing the observations into 
three periods: (1) 15 November 1943 to 1 January 1944; (2) 1 January 

1944 to 1 March 1944, and (3) 1 March 1944 to 1 April 1944. 

First Period of Prophylaxis. —An epidemic of influenza was exper¬ 
ienced during late November and December. At this time the incidence 
of carriers of hemolytic streptococcus was low and this organism failed to 
become active. The data collected in December are presented in table 
40. The rates for sick calls and dispensary admissions were comparable 
in the three treated groups and were lower than in the control group. 

Second Period of Prophylaxis. —The data for January are presented 
in table 41. It is seen in this table that the incidence of disease in each 
of the treated groups was lower than in the control group. The group 
receiving sulfadiazine, 1 gm. daily, had the lowest incidence of infections. 
The data for February are presented in table 42. It is seen in this table 
that the treated battalions had a lower incidence of disease than the con¬ 
trols and that a daily dose of 1 gm. of sulfadiazine appeared more effective 
than a similar dose given every second day. In the station forces a daily 
dose of 0.5 gm. appeared to lower the incidence of admission. 

Third Period of Prophylaxis. —On 1 March 1944 all station personnel 
were placed on a daily dose of 1 gm. of sulfadiazine. The control group 
was thereby abandoned. Efforts were concentrated on more careful clin¬ 
ical and bacteriologic studies of patients who developed disease while re¬ 
ceiving prophylaxis. Sample questioning was conducted to determine 
what percentage of men failed to take sulfadiazine and this number 
was found to be about 10 percent. A striking diminution of bacterial 
respiratory diseases occurred in March 1944. 


108 













Table 40 .—Statistical summary for month of December 1943 



* 






5-. 

t 


109 






















































110 

I 


♦ Batt. is Battalion and S. F. is Station Force 























































Table 42. — Statistical summary for month of February, 19^4 



111 


♦ S. F. is station force. 




























































Observations on Sulfadiazine Reactions 

Untoward reactions to sulfonamide were observed in a small percen¬ 
tage of cases. This varied in different groups between 1 and 4 per thou¬ 
sand. Most of the reactions were mild. The drug was discontinued for 
10 days in those with untoward symptoms and then most of the men 
were retested to determine whether they were truly sensitive to sulfona¬ 
mide. There were no serious or fatal reactions; one patient had an ulcer¬ 
ative stomatitis and bullous erythema on his hands. 

Observations on Gonorrheal Urethritis 

All patients taking sulfadiazine for 48 hours prior to exposure were 
considered to be in the treated group. Those who ingested sulfadiazine 
after exposure and those who received no sulfadiazine were placed in the 
control groups: 81 infections occurred; 8 of these were in the treated 
group and 73 in the control. The rates per thousand were 0.8 per 
thousand per month in the treated groups and 5.0 per thousand per month 
in the controls. Only 2 cases occurred in men taking a daily dose of 1 gm. 
The administration of 0.5 gm. daily as prophylaxis was ineffective. Some 
men who failed to have prophylaxis prior to exposure took 1 gm. of sul¬ 
fadiazine 24 hours later. This was also found to be ineffective. 

Laboratory Studies 

Two laboratory studies were made: bacteriologic examinations of the 
throat flora, and determinations of the sulfadiazine blood level. 

1. Throat cultures were studied of all patients with respiratory infec¬ 
tions. Standard technics were used for recovering and isolating hemo¬ 
lytic streptococcus in pure culture. Strains of this organism were shipped 
on blood agar slants to the National Naval Medical School for grouping 
and typing, and the results were returned to the station laboratory. None 
of the patients who contracted respiratory infections while on the sulfa¬ 
diazine prophylaxis program had group A hemolytic streptococcus in the 
throat flora. Group A strains were recovered from the untreated group 
with respiratory infections and were found to include many types: 14, 
36, 18, 30, 19, 6, and 1. No type showed any tendency to spread through 
this station during the winter and spring months of 1944. 

2. The sulfadiazine content of the blood was examined to determine: 
(a) whether sick personnel had lower blood levels than well person¬ 
nel; (b) whether the blood level reflected the prophylactic dose ingested; 
(c) whether an effective blood level is maintained for hours or days after 
the drug is discontinued; (d) whether persons developing sulfonamide 
reactions have unusual blood levels or unusual proportions of conjugated 
sulfonamide. The results are expressed in milligrams percent and pre¬ 
sented in tables 43, 44, and 45. 


112 


TABLE 43.— Sulfadiazine blood levels in cases admitted to dispensary 


Dose 

High 

Median 

Low 

Total cases 

1 gram dailv. __ 

4.9 

2.2 

Trace 

Trace 

57 

0.5 gram dailv-__. 

1.7 

1.2 

24 





Table 44. — Fall in blood sulfadiazine level on stopping prophylaxis 

of 1 grain daily 


Hours after discontinuance 

High 

Median 

Low 

Number o ' 

cases 

36.. 

1.6 

0.6 

Trace 

< 

48.-. 

1.0 

0.8 

0.6 

60. 

1.7 

0.6 

Negative 

Negative 

Trace 


72 . 

0.8 

0.5 

t 

96.. 

0.4 

0.2 

i 

IqR .. 

0.6 

0.6 

0.6 

1 

120 . . 

0.5 

0.2 

Negative 

Trace 

4 

136 .-. 

Trace 

Trace 

1 




Table 45.— Variations in free and conjugated sulfadiazine blood levels* 


Cases 

Total level 

Free level 

Conjugated 

Percent Con¬ 
jugation 

1 . 

1.9 

1 7 

0 3 

13.66 


4.9 

4 1 

0.9 

17.80 


2 1 

1 7 

0.5 

21.17 


1 6 

1 1 

0.5 

28.64 

6 . 

1 0 

C 5 

t 6 

55.78 

fi __ 

2.1 

2.0 

0.1 

6.62 

7 _ 

2 3 

1 6 

0.7 

30.30 

R _ 

3.2 

2.3 

0.8 

24.16 

q .... 

2.7 

2 3 

0.4 

16.37 

10 - - 

2.7 

2.1 

0.6 

23.33 


* All blood levels expressed as mg. %. 


113 






































































Table 46. —Comparison of rates of contagious diseases during 
January and February 1944 with January and February 1943 


Average daily population 

5104 

7019 

12538 


1944 treated 

group 

1944 untreated 

group 

1943 untreated 

Diseases 

Cases 

Rate * 

Cases 

Rate * 

Cases 

Rate * 

Cerebrospinal fever (meningococcic). 

0 

0 

4 

0.28 

69 

02.8 

Catarrhal fever, acute. ... 

29 

2.8 

191 

13.6 

1.926 

76.8 

U. R. I. 

37 

3.6 

243 

17.3 

2.022 

80.6 

Pneumonia, lobar, broncho.. 

1 

0.09 

12 

0.8 

13 

0.05 

Pneumonia, virus.. 

0 

0 

1 

0.05 

3 

0.01 

Scarlet fever. ..... 

0 

0 

0 

0 

3 

0.01 

All respiratory disease.. 

41 

4.0 

256 

18.1 

2,104 

83.9 

Gonorrhea... 

6 

0.7 

45 

3.2 

14 

0.05 

Infectious jaundice.-.. 

3 

0.3 

9 

0.6 

0 

0 

Measles—. 

7 

0.7 

9 

0.6 

24 

0.95 

Measles, German. 

16 

1.5 

5 

0.3 

186 

7.4 

Mumps. 

9 

0.9 

23 

1.6 

23 

9.1 

Rheumatic fever.•... 

0 

0 

5 

0.35 

3 

0.01 


♦Note: Rate per 1,000 per month. 


Table 47. —Statistical summary for months of January and February 1944 


Average daily population 

2,305 

1,423 

1,1115 

3,827 




1 gram every 





Dosage Schedule 

1 gram daily 

2 days 

0.5 gram 

Control 


battalion 

battalion 

daily 

battalion 

Diagnoses 

No. 

Rate 

No. 

Rate 

No. 

Rate 

No. 

Rate 

U. R. I.. 

9 

1.9 

10 

3.5 

15 

6.70 

120 

15.7 

All R. I. 

9 

1.9 

10 

3.5 

18 

8.07 

126 

16.5 

Scarlet fever.. 

0 

0 

0 

0 

0 

0 

0 

0 

Tonsillitis and pharyngitis. 

0 

0 

0 

0 

1 

0.9 

18 

2.3 

Pneumonia, lobar. 

0 

0 

0 

0 

0 

0 

a 


Cerebrospinal fever (meningococcus) 

0 

0 

0 

0 

0 

0 

1 

0.13 

Gonorrhea. 

0 

0 

2 

0.7 

4 

1.8 

13 

1.7 

Drug reaction... 

4 

0.1 

1 

0 3 

10 

4 5 












114 
























































CHART 33 



V. 

> ■ 



115 





















infectious Diseases During Winter of 1944 Compared with Winter of 1943 

A summary of the data on infectious diseases during January and 
February of 1943 and 1944 is presented in table 46. This table shows 
a striking improvement in the health on the station during the period of 
prophylaxis. The administration of sulfadiazine prophylaxis to half of 
the personnel lowered the number of susceptibles, and perhaps, this modi¬ 
fied the vulnerability of the “herd” to respiratory pathogens. 

Relation Between Dosage and Chemotherapeutic Effect 

Data on the disease occurring in groups receiving 1 gm. daily, 1 gm. 
every 2 days, and 0.5 gm. daily are presented in table 47. All three 
dosage schedules were effective in lowering the incidence of respiratory 
infections. A daily dose of 1 gm. of sulfadiazine was found necessary 
to prevent gonorrhea and was most effective in preventing respiratory 
tract bacterial infections. 

Comment 

Trainees at this station are more seasoned and of an older age group 
than those at most Naval training centers. On arrival they are placed 
in battalions. The housing of these battalions changes throughout their 
instruction. During a part of their course these men live on a range in 
the country several miles from the station. Their duties keep them out¬ 
doors a large part of the time. Perhaps for these and other reasons these 
men appear less susceptible to streptococcal infections than men at other 
Naval training activities situated within a radius of 100 miles. 

Although these trainees seem to have some protective mechanism for 
withstanding Streptococcus hemolyticus, they are, nevertheless, vulnerable 
to respiratory viruses. This is evidenced by the high rate of influenza 
in November and December 1943. Sulfadiazine prophylaxis has no 
apparent effect on virus infections. Sulfadiazine prophylaxis does, how¬ 
ever, lower the incidence of respiratory bacterial infections which occur 
following influenza. This is shown in chart 33. 

Conclusions 

1. Sulfadiazine prophylaxis prevented bacterial but not virus infections 
of the respiratory tract. Its effectiveness appeared to depend on the 
relative prevalence of these two types of infections. 

2. Sulfadiazine, 1 gm. daily, prevented between 80 percent and 88 
percent of respiratory diseases. 

3. Sulfadiazine, 0.5 gm. daily, was somewhat less effective. 

4. Sulfadiazine, 1 gm. daily, was 100 percent effective in preventing 
116 


meningococcal meningitis and hemolytic streptococcal throat infections at 
this station. 

5. Sulfadiazine, 1 gm. daily, was highly effective in preventing gon¬ 
orrhea; whereas, 0.5 gm. daily appeared to be of little or no protective 
value. 

6. The mean blood level for the gram daily dose was 2.2 mg. percent 
and for the daily 0.5 gm. dose was 1.2 mg. percent. 

7. Sulfadiazine prophylaxis, irrespective of the schedule of administra¬ 
tion, gave rise to mild untoward reactions in 0.3 percent of the cases. 


117 





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Report 7 

Control of Epidemic Upper Respiratory Diseases by 
Sulfadiazine Prophylaxis 

U. S. Naval Air Station Technical Training Center, 
Memphis, Tenn. 

From Epidemiology Unit 19"^ 


the first of February 1944 a program of sulfadiazine prophylaxis 
was instituted at the Memphis Naval Air Technical Training Center 
at the peak of a streptococcal outbreak. Twenty-four barracks, containing 
approximately 5,500 students, were selected at random and placed on a 
regimen of sulfadiazine, 1 gm. daily. Twenty-two barracks, housing 
about 4,900 students, were chosen to act as an untreated control group. 
Respiratory infections had been occurring in all these barracks and the 
severity of streptococcal infections had become disturbing. The mor¬ 
bidity rates for the last week in January (annual admission rates per 
thousand strength) were: catarrhal fever, 435; tonsillitis and pharyngitis. 
341 ; scarlet fever, 116; rheumatic fever, 4. 

Administration 

A line officer was assigned to each barracks to supervise the distribu¬ 
tion of sulfadiazine tablets. The Epidemiology Unit made spot checks 
to insure the efficiency of the distribution system. As far as could be 
determined, each man in the treated group received his drug. Occa¬ 
sionally, it was reported that a man did not swallow his tablets; however, 
these instances were rare. 

* Participants: Wm. V. Lulow, Lieutenant (MC) USNR; W. W. Kemp, Lieu¬ 
tenant (MC) J. W. Genet, Lieutenant, USNR. 

Assistants: E. A. Stone, Pharmacist, USNR; K. M. Hald, PhMlc, USNR; J. H. 
Dietrick, PhMlc, USNR; C. A. Donohue, PhM2c, USNR; E. M. Douglass. 
PhM2c, USNR. 


119 



Daily records were kept of the number of all ambulatory patients who 
complained of upper respiratory symptoms. Records of admission were 
obtained at the sickbay and hospital for all patients with respiratory 
symptoms, scarlet fever, tonsillitis or pharyngitis, pneumonia, meningitis, 
and rheumatic fever. 

Throat cultures were obtained from every man in the treated group 
who was admitted to the sickbay or hospital with an upper respiratory 
tract disease. In addition throat cultures were obtained in 10 percent 
of the untreated group with similar illnesses. These cultures of hemo¬ 
lytic streptococci were replated on a blood agar slant. Organisms were 
mailed in pure culture to the Streptococcus Typing Laboratory at the 
National Naval Medical School and the typing results were returned 
to this Unit. 

Clinical Observations 

The results of this streptococcal control program from 1 February to 1 
April 1944 are as follows: 

Upper Respiratory Tract Infections .—Prior tO' the institution of the 
sulfadiazine program, there was a high rate of respiratory infections 
throughout the entire station. The effect of sulfadiazine prophylaxis on: 
(a) the incidence of respiratory symptoms as observed at sick call is 
shown in chart 34; (b) the incidence of admissions to the dispensaries 
for minor respiratory diseases is shown in chart 35; (c) the incidence 
of admission to the hospital for severe respiratory diseases is shown in 
chart 36. These graphs indicate the effectiveness of sulfadiazine pro¬ 
phylaxis in preventing bacterial infections of the respiratory tract. 

Scarlet Fever .—Scarlet fever was controlled by sulfadiazine. Within 
the first week there was a sharp drop in the incidence of scarlatina in 
the group receiving prophylaxis. Only 3 cases occurred in March in the 
treated group; whereas 23 cases appeared among the controlled person¬ 
nel. Morbidity rates are shown in chart 37. From our experience dur¬ 
ing the first 9 weeks of the study, it appeared -that fairly conclusive evi¬ 
dence was obtained as to the effectiveness of sulfadiazine prophylaxis in 
the prevention of scarlet fever. 

Tonsillitis, Pharnygitis, and Catarrhal Fever .—The striking difference 
in the incidence of these diseases observed between the treated and un¬ 
treated groups is shown in charts 38 and 39. Sulfadiazine reduced the 
incidence of these illnesses beginning with the first week of the prophy¬ 
laxis program. 

Meningitis .—Meningitis was completely controlled. During the 2 
months of this study, seven cases of meningitis occurred among untreated 
personnel; none appeared among the treated group. 

Rheumatic Fever .—Chart 40 shows the incidence of rheumatic fever 
during February and March. The program of sulfadiazine prophylaxis 

120 




CHART 34 


flu Upper Kespir«to»y tXiektei 
Suifkdibf i ne Frop/>yl«*p s~ri/\TTC' Mrinphij, fenn 

DAILY SICK-CALL RCPOKT 

(Ctt^cj p*r rKvu^hnd. per WrtKJ 

Solid Lme** "Treated (iqram iu.1 ae d*ily) 

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0.00 Data 

4-u o-« tp'tfc ei~M*r.t f-M ijL-n n-jr MrA»»i »■$ »*u *»•»*< 


121 





122 


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Table 48. —Rheumatic fever vnth rates per thousand per week*, 
treated and untreated groups 



Treated 

U ntreated 

Date 

No. cases 

Rate per 
1,^00 

No. cases 

Rate per 
1,000 

Feb. 1-fi ..... 

1 

.19 

2 

.41 


1 

.18 

0 

.00 

13-19 ... 

4 

.71 

2 

.42 


4 

.71 

6 

1.22 

Feb. 27-Mar. 4 . 

2 

.36 

1 

.20 

Mnr. P-11 .. 

1 

.18 

3 

.59 

1^>-18 ___ 

2 

.35 

5 

.98 

19-25. 

1 

.18 

7 

1 .4 

April 1 ___ 

0 

.00 

4 

.83 





Total .— -. 

16 


30 






Table 49. —Drug reactions classified as to type 


Description 

Number of 

cases 

Average 
amount of 
drug 
ingested 
(grams) 

Generalized morbilliform of punctate rash. 

41 

26 

Urticaria......... 

* 12 

19 

Edema.. ..... 

*3 

23 

Headache, nausea and vomiting.. 

4 

43 

Agramilocvtosis .. 

1 

58 

Stomatitis . .. 

1 

6 




♦ 1 case exhibited both edema and urticaria. 


had been designed to reduce the incidence of bacterial respiratory infec¬ 
tions, particularly those caused by hemolytic streptococci. The institu¬ 
tion of the program was accompanied by a significant drop in the number 
of respiratory infections. This was followed by a progressive disappear¬ 
ance of rheumatic fever in the treated group. Table 48 gives the number 
of cases and the rates in the treated and untreated groups, by weeks, 
since the program of sulfadiazine prophylaxis was begun. 

The first month of sulfadiazine prophylaxis could not have been ex¬ 
pected to reduce the number of cases of rheumatic fever because the hem¬ 
olytic streptococcal infections which precipitated the February cases of 
rheumatic fever had already occurred. In the first 4 weeks of prophy¬ 
laxis, each group had 10 cases; whereas during the last 5 weeks, only 6 
cases appeared in the treated group and 20 cases appeared in the un¬ 
treated group. 


128 












































Pneumonia .—Sulfadiazine prophylaxis had little if any effect on the 
rate of pneumonia. Cases of pneumonia at this station during February 
and March were diagnosed as primary atypical pneumonia with few ex¬ 
ceptions. 

Gonorrhea .—Following the institution of sulfadiazine prophylaxis, it 
was noted that the incidence of gonorrhea was greatly reduced. The 
rates of infections among all Negro personnel receiving prophylaxis were 
at the lowest point ever seen on this station. 

Drug Reactions 

Drug reactions during the 2 months of this study totaled 61. Of these, 
1 case appeared to be granulocytopenia. The patient is still under study 
and is making an uneventful recovery. The data on sulfadiazine reac¬ 
tions are tabulated in table 49. 

Results of Typing 

Forty-eight strains of hemolytic streptococci were sent to the Labora¬ 
tory at the National Naval Medical School. The most prevalent sero¬ 
logic types were 19 and 17. Types 3, 1 and 36 were recovered from 
several throats. Other types present were 2, 5, 6, 14, 24, and 41. 

Conclusions 

The following conclusions are drawn from the observations made dur¬ 
ing the administration of 1 gm. of sulfadiazine daily to half of the enlisted 
personnel at Memphis Naval Air Technical Training Center in February 
and March, 1944. 

1. Mild bacterial respiratory tract infections, not requiring hospitali¬ 
zation, were reduced in incidence. 

2. Tonsillitis and pharyngitis were markedly reduced in incidence. 

3. Scarlet fever was almost entirely prevented. 

4. Rheumatic fever persisted during the first 4 weeks of prophylaxis, 
then declined progressively and was not observed during the last week 
of this study. 

5. Meningitis (meningococcal and streptococcal) was entirely pre¬ 
vented. 

6. Gonorrhea was greatly reduced in incidence. 

7. Pneumonia (atypical) was not prevented. 

8. Drug reactions occurred in 0.6 percent of men treated over a period 
of 9 weeks. All reactions but one were mild. 


129 






Report 8 


Mass Prophylaxis of Respiratory Disease 

U. S. Naval Air Technical Training Center, Norman, Okla. 

From Epidemiology Unit 43"^ 

T he Streptococcal Control Program instituted at the Norman base was 
an attempt to explore the efficacy of sulfadiazine in mass prophylaxis 
during a severe outbreak of streptococcal diseases. It was hoped that 
some rational evaluation of the drug in this role might be made on the 
basis of clinical and epidemiologic data without recourse to elaborate 
laboratory facilities. The data reported herein consequently represent 
the observations of a group of clinical workers. 

Methods 

Four groups, designated hereafter as groups A, B, D, and E, were 
selected for observation in this program. Each group comprised from 
2,000 to 3,000 men, enlisted personnel. Inasmuch as no atternpt was 
made at selection within groups, it may be presumed that there was no 
significant difiference in age, geographic origin, or racial stock. Each 
group consisted primarily of trainees in aviation ordnance, metalsmith 
work and mechanics, and was subjected to the same or similar hazards 
of weather and occupation. Although each group was quartered in its 
own regimental area, these regimental areas we're separated only by a 
dividing street. Although the areas were adjacent, there was little oppor¬ 
tunity for mingling of trainees from different groups or areas; the stag¬ 
gering of classes, duty, and liberty undoubtedly reduced to an insignifi¬ 
cant factor the mingling of men from different areas. In only one re¬ 
spect did the groups represent a specific difference: Group D was com- 

* Participants: Donald C. Young, Lieutenant Commander (MC) USNR and 
James M, Ruegsegger, Lieutenant Commander (MC) LFSNR. 

Assistants: W. G. Fee, PhMlc; E. G. Karch, PhMlc; L. C. Daniels, PhM2c; 
M. Lederman, PhM2c; M. E, Leary, PhM3c. 


131 



posed exclusively of Marines; whereas members of the other groups be¬ 
longed to the Navy personnel. 

Observations concerning the respiratory health of these trainees were 
made at the dispensaries of the station. Sick Call for respiratory dis¬ 
orders was held at only two of the dispensaries; a daily census of these 
calls was recorded by analyzing the diagnosis from the sick-call chits of 
new patients. The majority of the moderately ill patients were admitted 
to the sickbay of Dispensary 34 which was staffed by members of the 
Epidemiology Unit. The acutely ill patients were admitted to the U. S. 
Naval Hospital. These patients were visited daily by some member of 
the Unit to confirm diagnoses and take cultures. In this manner, a reas¬ 
onably accurate morphologic diagnosis and record of disease of the respir¬ 
atory tract could be made. These diagnoses included coryza, rhinitis, 
pharyngitis, tonsillitis, streptococcus infection of the throat, cerebrospinal 
fever, catarrhal fever, rheumatic fever, and the various kinds of pneu¬ 
monia. The four groups were observed for 3 weeks to ascertain a base¬ 
line of health or morbidity for trainees. As a control, group A was se¬ 
lected not to receive the drug. 

Each of the personnel of the three remaining groups B, D, and E 
received 1 gm. of sulfadiazine daily after 17 February 1944. Many ad¬ 
ministrative details, some of which were not anticipated, presented them¬ 
selves and the most vigilant supervision was indicated. Close coopera¬ 
tion with the regimental commanders was essential to reduce the errors 
to a minimum. Some of these are enumerated and described in order to 
disclose the pitfalls in the proper evaluation of this type of clinical re¬ 
search. 

The untreated group A was neither informed of its control role nor 
were blank pills issued to them. The ready accessibility of the sulfon¬ 
amides makes self-medication of minor respiratory disease not exceptional; 
several such instances were disclosed and it is impossible to evaluate that 
factor in the morbidity rate of the control group. Among the groups re¬ 
ceiving the drug as a prophylactic, all sorts of subterfuge were uncovered 
by tactful investigation. Examination of the oral cavity following inges¬ 
tion of the tablets was employed at some of the musters but such a pro¬ 
cedure becomes impracticable as a daily procedure among 6,000 or more 
men. Similarly, week-end liberty inevitably increased the number of in¬ 
stances of noncooperation. The latter difficulty was partly obviated by 
the administration of 2 gm. of the drug each Saturday to all men having 
week-end liberty. Blood chemical determinations were not made to 
ascertain the presence of a residual effective level before the next regular 
dose was administered. Fear of untoward reactions was not a significant 
motive among those failing to cooperate. On the other hand, the project 
did not have the influence of fear of an epidemic in securing cooperation. 

132 


Laboratory studies consisted of taking throat cultures and, in a few 
instances, the culture of otic and pulmonary exudate. Except in cases of 
typical pneumonia, principal interest in these cultures was in the identi¬ 
fication and typing of hemolytic streptococci. Throat cultures were taken 
from all patients admitted to the sickbay or hospital from groups B, D, 
and E. Sampling of group A was accomplished by taking cultures from 
approximately 10 percent of the patients in this group. 


Table 50 .—Consolidated rates for respiratory infections 
before and during prophylaxis 



Three control weeks 

Twelve prophylaxis 
weeks 


A 

B-D-E 

A* 

b-d-e** 

Respiratory complaints.. 

241.0 

233.2 

452.00 

227.4 

Respiratory illnesses admitted to dispensaries. 

63.2 

42.4 

63.60 

29.4 

Respiratory illn3sses admitted to hospital.. 

12.1 

8.24 

11.64 

7.09 

Scarlet fever._... 

6.05 

3.12 

6.22 

2.53 

Tonsillitis or pharyngitis or both. 

24.2 

24.6 

28.60 

7.97 

Pneumonia. 

0.81 

1.43 

7.23 

7.20 


* A was control group. ♦* B-D-E received chemoprophylaxis. 


Results 

The accumulated data are shown in table 50. A more striking analysis 
may possibly be made by referring to the weekly morbidity rates as judged 
by the number of patients visiting the dispensaries with symptoms of 
respiratory disease. These rates are shown in table 51; the rates for the 
corresponding periods in 1943 are shown in the same table for com¬ 
parison. The weekly rates for 1944 are shown in chart 41. Although 
there occurred a general reduction in the morbidity rates about the time 
the prophylaxis was instituted, a sharp reduction in the rates of groups 
B, D, and E was observed within 1 week of the institution of this pro¬ 
gram. This reduction was- maintained throughout the period of pro¬ 
phylaxis. Subjecting these figures to significance tests, it is shown 
unequivocally that some factor other than chance is responsible for the 
disparity in attack rates between the two groups after 17 February. 

A similar difference is shown in the attack rates for scarlet fever and 
acute pharyngitis (including tonsillitis). These diseases are due almost 
exclusively to organisms which are usually sensitive to the inhibiting 
influence of the sulfonamides; therefore, this comparison represents a 
more decisive trial of the drug than the inclusion of all respiratory dis¬ 
ease. The attack rate of these diseases was more than 3 times as great 
among the trainees in group A as among those receiving the prophylactic 
drug; in this instance also such a difference in attack rates is not acci¬ 
dental. 


133 


















51 —Respiratory infections: attack rate per thousand 



134 


Areas B-D-E received chemoprophylaxis from February 17 to May 80, 
Area A served as a control group. 











































































































The number of infections due to the Neisseriae was too small to war¬ 
rant comparison. Five cases of meningococcal meningitis were observed 
among the 10,000 odd trainees during the 3 weeks’ control period before 
the drug was administered prophylactically. In the succeeding 10 weeks, 
a single case was observed, and the patient was admitted to the dispensary 
a few hours after the first distribution of sulfadiazine. 

It will be observed from table 50 that the number of cases of pneu¬ 
monia increased during the period of sulfadiazine administration; more¬ 
over, the pneumonia morbidity rate increased in each group without any 
apparent pattern of increase. Further inspection of this group of cases 
discloses an explanation for this apparent paradox. Of the entire series 
of pneumonia cases, only five were shown to be of bacterial origin; pneu¬ 
mococci of Type I were found in 2 instances; Type II in 2 instances, and 
Type V in a single case. Most of the remaining cases of pneumonia 
conformed to the clinical and roentgenologic description of primary 
atypical pneumonia, cause unknown, and none of these showed a satis¬ 
factory clinical response to the sulfonamides. If the causative agent of 
this group is a virus, as many investigators believe, there is little reason 
to expect an inhibiting effect from the sulfonamides. 

Bacteriology 

The results of the bacteriologic studies, as they pertain to the strepto¬ 
coccus, are shown in table 52. There are insufficient typings to warrant 
positive generalizations. It appears that during this period Type 17 was 
the most prevalent. No single type is found regularly as the causative 
agent in any given clinical entity. It might be significant that in only 7 
instances were hemolytic streptococci isolated from pneumonia patients 
and in 2 of these instances the patients undoubtedly had typical pneu¬ 
mococcal pneumonia. 


Table 52. — Serologic types of group A hemolytic streptococcus 
recovered from respiratory infections 



135 




















































Sulfadiazine Reactions 


Untoward reactions were infrequent following the daily ingestion of 
the drug. No deaths occurred among the trainees during the period of 
observation. All patients who presented symptoms suggesting an intol¬ 
erance of the drug were seen by a member of the Epidemiology Unit. In 
several cases patients were interviewed and examined who complained of 
gastro-intestinal disturbances. In each case, some other factor was dis¬ 
closed and the drug was not discontinued in a single instance because of 
real or fancied gastro-intestinal symptoms. Cases of toxicity involving 
the hematopoietic system were not observed. 

As might be expected, the only significant untoward reactions seen were 
those manifested by a skin eruption. Fifty-one trainees were examined 
who presented local or generalized dermatitis. For the greater part, 
these rashes were morbilliform, and in a few instances, it was almost 
impossible to differentiate the eruption from German measles. Likewise 
in an occasional case, the differential diagnosis from scarlet fever was 
perplexing on an exclusively morphologic basis. Two cases resembled 
the erythema nodosum rash characteristic of sulfathiazole dermatitis; in 
neither case did the skin present a subcutaneous nodule on palpation. 
Conjunctival injection was seen in several instances accompanying a 
generalized eruption. 

Because of the pleomorphism of sulfonamide skin reactions, an attempt 
was made to confirm the original impression by reproducing the lesion 
after an interval of from 7 to 14 days. Of these 51 cases, the dermatitis 
was reproduced later in 17 instances by the administration of small daily 
amounts of the drug. In most cases, the eruption reappeared after 1 or 
2 gm. given in daily doses of 0.5 gm.-l gm. It may be speculated that 
the remaining patients had been desensitized by the further or continued 
ingestion of the drug. Until some reliable immuno-chemical tests are 
available, the question of sensitivity to the sulfonamides will probably 
remain controversial. 

Further observations were made concerning sulfonamide sensitivity in 
those patients who had reproducible skin lesions. After an interval of 
from 1 to 4 weeks, fifteen of these patients were administered the mono- 
methyl derivative (sulfamerazine) of sulfadiazine in daily doses of 1 gm. 
At the time of the completion of this program, only three had shown a 
reaction to this derivative. This observation is in agreement with the 
observations of others that these so-called sensitivities to the sulfona¬ 
mides are specific and show little cross-reaction, even to isomeric forms. 
Such observations emphasize not only the urgency but also the value of 
informing the patients of their reactions. It seems equally important to 
record these observations in the individual health record, so that need¬ 
less and possibly serious reactions might be prevented at a later occasion. 


136 


CHART 41 



WttK OF OeS£»VAT»ON 


Conclusions 

1. The administration of 1 gm. of sulfadiazine daily for 12 weeks to 
approximately 8,000 Naval trainees effected a significant reduction in the 
incidence of respiratory disease. 

2. This effect was not noted for virus diseases or those suggesting virus 
origin. 

3. The daily administration of 1 gm. of the drug caused skin rashes 
in not more than 51 trainees, an incidence of considerably less than 1 
percent. 

4. No severe untoward effects were seen following the daily adminis¬ 
tration of 1 gm. of sulfadiazine and only 17 trainees were excused from 
the program because of dermal reactions. 


137 



































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-A# 







Report 9 

The Streptococcal Control Program 
Navy Pier, Chicago 

From Epidemiology Unit 89"^ 


#% program for the prevention of respiratory diseases, especially those 
caused by Streptococcus hemolyticus, was initiated 8 February 1944. On 
this date the indications for a Streptococcal Control Program at this 
Naval activity was striking. During December 1943 more than 25 per¬ 
cent of the station’s complement had been admitted to the sick list with 
respiratory infections; a total of 27,966 man-days, 10 percent of the 
available manpower, was lost. The incidence of these infections con¬ 
tinued to be high in January, and a large number of men developed rheu¬ 
matic fever. By 1 February 1944 the annual admission rate had reached 
extraordinary heights: for rheumatic fever, 70; for scarlet fever, 171; for 
tonsillitis, 426; and for catarrhal fever, 988. The urgency of the situa¬ 
tion and the expectancy of an increase in the prevalence of streptococcal 
infections during February and March were strong indications for placing 
all enlisted personnel on a program of sulfadiazine prophylaxis. 

It was believed that a controlled study would be unwise and that 
streptococcal rates at other Naval activities in the Chicago area would 
serve as an indicator of the prevalence of these infections. The present 
report deals with the effect of sulfadiazine prophylaxis on respiratory 
infection rates during February and March, 1944 at Navy Pier, Chicago. 


* Participants: Douglas S. Damrosch, Lieutenant (MC) USNR; Byron D. 
Casteel, Lieutenant (MC) USNR; R. G. Lapenta, Lieutenant (MC) USNR 
(Epidemiology Unit 13); George C. Morris, Lieutenant (jg), H-V(S) USNR. 

Assistants: P. R. Carter, PhMlc; USNR; W. F. Alston, PhM2c, USNR; C C. 
Ball, PhM2c, USNR. 

Acknowledgements: To Captain T. H. Taber, (MC) USN; Captain H. A. 
Noreen, (MC) USN; and the Medical Officers at the Navy Pier for their co¬ 
operation in the administration of the program. 


139 



Administration 


First, all the details for administering sulfadiazine prophylaxis were 
explained to the line officers in charge of the several companies into which 
the station personnel is divided. A supply of sulfadiazine was delivered 
to the regimental office weekly and thence to the various company com¬ 
manders. Each man on the station was then ordered to take 1 gm. of 
sulfadiazine in a single daily dose. This was issued by company officers 
or responsible petty officers at an hour when the company could be mus¬ 
tered conveniently; most companies elected early morning, just prior 
to the beginning of classes. Two grams of sulfadiazine were administered 
each Saturday and none was given on Sunday. Incoming draftees were 
automatically started on the drug regimen on arrival. Through their 
officers, all men were instructed to report immediately to the sickbay on 
the appearance of a rash or when noticing any change in their general 
health. In the sickbay, the medical officers of the station referred all 
patients with probable drug reactions to a medical officer of the Unit who 
attended daily sick call. 

Examinations of Throat Flora 

Throat cultures were studied of 40 men who contracted respiratory 
infections during this 2-month period; in 31 of these there were no hemo¬ 
lytic streptococci in the throat flora; in 9 this organism was found in 
cultures of the nasopharynx; 5 of these were diagnosed as catarrhal fever; 
3 tonsillitis, acute, and 1 scarlet fever. The strains of hemolytic strepto¬ 
cocci isolated from these men were shipped to the National Naval Med¬ 
ical Center where the serologic types were identified as 17, 3, 30, 1, 5, 
and 36. 

Study of Untoward Reactions to Sulfadiazine 

Each patient with symptoms attributable to sulfonamide was examined 
and then given a card excusing him from the prophylactic program. In 
from 10 days to 2 weeks he was called back for retesting. This was done 
by having him report on 4 consecutive days. On the first day the patient 
was given sulfadiazine, 0.5 gm., and on the following day, 1 gm. If any 
toxic manifestation appeared within this period, the patient was removed 
from the program and an entry was made in his health record indicating 
that he was sensitive to sulfadiazine. If no untoward reaction occurred, 
his card was taken and he was again placed on the sulfadiazine program. 

Altogether 131 men reported to sickbay where they were studied for 
possible drug reactions. Histories were taken to determine their previous 
experience with sulfonamides, the length of time on the Streptococcal Con¬ 
trol Program, and previous manifestations of idiosyncrasy. Urine exami¬ 
nations and complete blood counts were made; all proved to be normal. 

140 


*-*&“*- oiviii \aiacci3ca iiuL dsauciciLcu wiLu suuuiiciiriiues 

(psoriasis, pityriasis, scabies, eczema, acne vulgaris, and fungus infec¬ 
tions). Sixty-three who were apparently drug-sensitive were retested 
with sulfadiazine. Twenty-eight were found to be sensitive to the drug. 
Thirty-five remained symptom-free and were returned to the program. 
None of these has reported back with drug reactions. On the basis of 
those retested, it is probable that approximately one-half of those orig¬ 
inally seen were actually sensitive, a rate of 0.3 percent. 

The toxic manifestations to sulfadiazine varied considerably. The 
most common one seen was a maculopapular erythematous rash (accom¬ 
panied by pruritus in half the cases), particularly prominent on the flexor 
surfaces of the extremities, medial aspect of the thighs, and on the lateral 
aspect of the thorax. The next most common manifestation was a finely 
granular scarlatiniform rash with similar distribution. In four cases 
this type of rash was accompanied by chilly sensations, nausea, and fever 
ranging from 102“ F. to 104° F. In all cases fever and symptoms sub¬ 
sided within 24 hours after sulfadiazine administration was discontinued. 
A number of cases of urticarial reactions were also seen. In two cases 
there was a rash limited to the legs and characterized by numerous small, 
discrete purpuric spots. 

There was no correlation between the severity or type of reaction and 
the number of days on the drug program. About 50 percent of the sen¬ 
sitive patients had received therapeutic doses of sulfonamides in the past 
and 73 percent of these had experienced toxic manifestations during 
therapy. Three had multiple idiosyncrasies. 

Results 

The institution of sulfadiazine prophylaxis at the Navy Pier was fol¬ 
lowed by a rapid fall in the incidence of disease. The scarlet fever rate, 
for example, fell weekly to 70, 45, and during the third week to zero. 
The rheumatic fever rate rose during the first week to 87 and then fell 
progressively to 45, 45, 19, and 6. This improvement was not to be ex¬ 
pected during February and March, and the weekly rates for scarlatina 
and rheumatic fever at other Naval activities in Chicago rose during this 
period. 

Four charts will serve to illustrate the effectiveness of sulfadiazine at 
the Navy Pier: Chart 42 on the daily admissions to the sick list; chart 
43 on morbidity from respiratory infections, chart 44 on the incidence 
of scarlet fever and rheumatic fever; and chart 45 on the morbidity from 
respiratory infections in comparison with five other activities in the 
Chicago area. 

Chart 42 shows a day-to-day record of admissions to the sick list at 
the Navy Pier for the following diseases: Tonsillitis, pharyngitis, ca¬ 
tarrhal fever, scarlet fever, rheumatic fever, pneumonia (all forms), acute 


141 


CHART 42 



142 


















































































































































CHART 43 



143 










































































































CHART 44 


to O ^ 




144 












































































































CHART 45 





2 2 2 2 2 ® 

~ NSH^or a 3d' saxvtf 


145 







































































































































































































sinusitis, laryngitis, acute otitis media, Vincent's infection, acute bronchitis, 
acute pyogenic meningitis, and acute mastoiditis. The points of this 
chart represent absolute numbers and not rates. There was a rise in the 
average strength of the station in February over January, and a small 
decrease in strength in March. 

Chart 43 shows the monthly morbidity rates for the diseases mentioned 
during the current winter (1943-1944) in comparison with those for the 
previous winter. It will be noted that during the months of November, 
December, and January of the current winter the rates were considerably 
higher than for the corresponding months of the previous winter. This 
relation was reversed in February, when the sulfadiazine program was in 
progress for 21 out of 29 days, and this reversal was most pronounced 
in March, when the program was in effect for the entire month. During 
this period there were no changes in the general health program of the 
station, no improvement in housing facilities, and no reason other than 
sulfonamide to which the decrease in morbidity might be attributed. 

Chart 44 shows the rates for scarlet fever and for rheumatic fever 
during the past winters. It is again evident that the incidence of 
these two diseases, both of which provide an indication of the incidence 
of streptococcal infections, was higher by a wide margin during the early 
months of the current winter than in the corresponding months of the 
preceding winter. In the light of the previous winter’s experience, there 
was every reason to expect a high incidence for both diseases in March, 
1944; however, the rates for both diseases fell to a lower level in March, 
1944 than in the previous March and in the preceding months of the 
current winter. 

Chart 45 shows the morbidity from respiratory diseases at the Navy 
Pier and at five other Naval activities in Chicago. The average strength 
for the Navy Pier during the period studied is approximately that of the 
other activities combined. Although these other groups are not entirely 
comparable to the group at Navy Pier, all these activities are training 
schools with a. turnover of personnel between 3j4 weeks and 4 months, 
and all are located in an area where respiratory infections have been 
particularly prevalent during the period of observation. The morbidity 
rates of these activities, therefore, serve as an indication of the month- 
to-month trend in the incidence of respiratory diseases in Chicago. It 
is seen in chart 45 that the incidence of these diseases during February 
and March fell only at the Navy Pier. In March, the first full month 
of sulfadiazine prophylaxis, the incidence of respiratory disease at the 
Navy Pier was by far the lowest of any naval activity in Chicago, 

146 



Summary 


1. The incidence of respiratory tract infections was high at the Navy 
Pier in the winters of 1943 and 1944. 

2. In January, 1944 streptococcal infections at the Navy Pier seriously 
handicapped this activity and gave rise to a high incidence of rheumatic 
fever. 

3. The institution of sulfadiazine prophylaxis was followed by a prompt 
fall in the rate of respiratory infections, including scarlet fever, and a 
progressive fall in the incidence of rheumatic fever. 

4. In March, 1944 when the incidence of respiratory disease, scarla¬ 
tina, and rheumatic fever was high at Naval activities in the Chicago 
area, it was minimal at the Navy Pier. 

5. This precipitous decline in the incidence of these diseases during 
February and the maintenance of these low rates during the spring 
months at Navy Pier is attributed to the effectiveness of sulfadiazine in 
preventing bacterial infections of the respiratory tract. 

6. The incidence of drug reactions was 0.188 percent in February and 
0.375 percent in March. About 40 percent of the men retested were 
found sensitive. No severe reactions occurred. 


147 





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Conclusion 


Mass Chemoprophylaxis 

The U. S. Navy's Six Months' Program for the 

Control of Streptococcal Infections 

Commander Alvin F. Coburn (MC)V(S), U.S.N.R. 


Altogether throughout this program more than 600,000 Naval trainees 
received daily doses of sulfadiazine to protect them from respiratory 
diseases. The results of 6 months’ observation permit an appraisal of 
this prophylactic measure. Before attempting to weigh the advantages 
and disadvantages of this strategy for attacking respiratory pathogens, 
one must first understand the nature of the problem at the Naval training 
activities that instituted this Streptococcal Control Program, 

The Problem 

A high morbidity rate for hemolytic streptococcal infections occurred 
in the U. S. Navy during the first quarter of 1944. The distribution of 
Naval activities with a high incidence* of diseases believed to be of 
streptococcal origin is shown in charts 46, 47, and 48 in which are indi¬ 
cated stations that had an extremely high, a moderately high, or a high 
disease rate for several weeks of the winter months. 

The distribution of scarlet fever was similar to that of tonsillitis and 
pharyngitis. High rheumatic fever rates occurred where the rates for 
one or all of these respiratory diseases were high. The Thirteenth and 
Ninth Naval Districts consistently showed the highest morbidity rates 
for all these infections throughout January, February, and March of 1944. 

No two stations had identical or, with one exception, even similar 
problems: 


* Data obtained from weekly morbidity rates expressed in annual admission rates per 1,000 
strength. 


149 



1. At Farragut, respiratory diseases had proved a menace in 1943. 
Strains of hemolytic streptococcus had acquired an alarming degree of 
pathogenicity. The micro-organism appeared to be almost as communi¬ 
cable as respiratory viruses. At one time 8 percent of all personnel were 
on the sick list because of streptococcal diseases. In one year, hemolytic 
streptococcus had precipitated about 5,000 cases of scarlet fever and 
1,500 severe rheumatic attacks. Its virulence was maintained during the 
summer months and within a few weeks after the onset of winter, there 
were more than 200 cases of primary streptococcal pneumonia. Its ac¬ 
tivity in these patients and in those developing rheumatic fever was fol¬ 
lowed by a high incidence of incapacitating disease. The problem was 
to check the epidemic process quickly, so that this station might continue 
to function. 

2. At Great Lakes, strains of hemolytic streptococcus had caused a tre¬ 
mendous loss in man-days during the winter and spring months of 1943. 
With increasing numbers of personnel in training, there were good indi¬ 
cations that the morbidity rate as a result of respiratory diseases would 
increase throughout the winter and spring months of 1944 unless meas¬ 
ures were instituted to control scarlet fever, tonsillitis, and rheumatic 
fever. 

3. At Sampson, hemolytic streptococcus had manifested great activity 
shortly after the opening of the station. The pathogenicity of the micro¬ 
organism apparently subsided during the summer months. The ob¬ 
jective was to prevent any strain from acquiring virulence. 

4. At Davisville, hemolytic streptococcus had not proved to be a 
menace; however, the station is situated on the New England coast 
where streptococcal infections are likely to occur. The problem there 
was to prevent the entry of hemolytic streptococcus. 

5. At Bainbridge, several serologic types of hemolytic streptococcus 
had manifested varying degrees of pathogenicity during the spring months 
of 1943. Type 19 regained considerable activity in the fall months. The 
problem there was to suppress this micro-organism which had spread 
throughout the station. 

6 and 7. The Naval Air Technical Training Centers at Norman and 
Memphis were severely crippled by streptococcal infections in December 
1943 and January 1944 when vicinal Naval and civilian activities were 
having exceptionally low streptococcal morbidity rates. Both of these 
stations had experienced epidemic influenza in the fall months of 1943’ 
and this had been followed by serious streptococcal infections. About 6 
percent of all personnel were on the sick list in Jamiary, and primary 
streptococcal pneumonia with its suppurative complications had rriade its 
appearance. The problem at each of these stations in January 1944 was 
to check an epidemic caused by highly virulent strains of hemolytic 
streptococcus. 


150 




THE DISTRIBUTION OF U. S. NAVAL ACTIVITIES WITH HIGH 
MORBIDITY RATES FOR SCARLET FEVER IN THE 

WINTER OF 1944 


CHART 46 



N 


151 


































THE DISTRIBUTION OF U. S. NAVAL ACTIVITIES WITH HIOH 
MORBIDITY RATES FOR PHARYNGITIS AND TONSILLITIS IN THE 

WINTER OF 1944 


CHART 47 





1 


I 

1 






152 























THE DISTRIBUTION OF U. S. NAVAL ACTIVITIES WITH HIGH 
MORBIDITY RATES FOR RHEUMATIC FEVER IN THE 

WINTER OF 1944 



153 


WEEKLY MORBIDITY RATE OVER SO 
WEEKLY MORBIDITY RATE IB- tO 
WEEKLY MORBIDITY RATE 10. IB 















8. At Navy Pier, Chicago, the training of personnel had become 
seriously handicapped in December 1943. That station had experienced 
a high incidence of streptococcal infections in previous winters with sub¬ 
sequent high rheumatic fever rates. Late in 1943, it appeared that path¬ 
ogenic strains had become exceptionally active prior to the onset of winter. 
During December 1943, more than 25 percent of the station’s complement 
were admitted to the sick list because of respiratory infections. The 
objectives of prophylaxis at that activity were to check a well advanced 
streptococcal epidemic and to prevent the implantation of other strepto¬ 
coccal strains during the spring months of 1944. 

Hemolytic streptococcus, although the most important, was not the 
only respiratory pathogen causing concern at those several stations. 
Meningococcus had caused an epidemic at Davisville, and fulminating, 
fatal disease at other activities. Pneumococcus had been the causative 
agent in most of the cases of pneumonia at stations that experienced cold 
winters. Gonococcus had caused considerable morbidity among groups 
who had finished “boot” training and rated liberty. 

Factors in the Pathogenesis of Respiratory Epidemics at 
Naval Training Centers 

Five conditions favoring the development of respiratory epidemics were 
satisfied at each of these training centers: (1) Fresh, highly susceptible 
recruits were introduced almost daily; (2) there was a high rate of change 
in population during the program for rapid training; (3) overcrowding 
and the congestion of large numbers of men in sleeping quarters occurred; 
(4) outbreaks of influenza or measles developed either prior to or during 
the prophylactic program; (5) most of the training centers were seeded 
with strains of respiratory pathogens which had already shown extreme 
communicability. 

Other less obvious factors, which varied from station to station, were 
also operative. At some, high temperatures with extremely low humid¬ 
ities were maintained in the barracks during the winter months. At 
others, dust storms presented a serious local problem. Rapid fluctuations 
in outdoor temperatures, rain, snow, fog, and other climatic states were 
variables at each activity. Many of these conditions, not subject to ap¬ 
praisal, were unfavorable to the normal, physiologic responses of the host, 
and, therefore, were favorable to the invasion of bacterial respiratory 
pathogens. 

It was possible to anticipate that respiratory pathogens would be 
prevalent at Naval training activities in times of war; nevertheless, pre¬ 
ventive medicine has not yet mobilized the forces necessary to prevent 
a high incidence of communicable diseases during the rapid expansion of 
training programs. The reasons are obvious: Training large numbers 
of recruits with inadequately developed facilities precludes the execution 

154 



of well established principles of good hygiene, and there are many factors 
inherent in the pathogenesis of these diseases to be controlled. 

The significance of some of these modes of infection is becoming more 
and more apparent: 

1. The contamination of meat and milk has long been recognized as a 
cause of explosive outbreaks. 

2. The direct transmission of respiratory pathogens from infected per¬ 
sons during the incubation and convalescent states is accelerated by over¬ 
crowding and billeting in times of war. The use of double-decked bunks 
permits the direct transmission of large inocula of bacteria from man to 
man. 

3. The possibility of insufflation of infected particulate matter occurs 
with intensive recruit training in swimming. One man plunges into the 
water of a pool and contaminates it with purulent exudate from the nasal 
sinuses or the respiratory tract. This material, uninfluenced by short 
exposure to chlorine, may be forced under pressure into the ears, sinuses, 
or respiratory passages of the recruits who follow in quick succession. 
The chlorination of swimming pool water may give little protection under 
these conditions, although aflFording a satisfactory bacterial count on 
analysis. Furthermore, chlorine acts as an irritant to the mucous mem¬ 
branes of many persons. This may be one of the several factors in swim¬ 
ming which lower the resistance of mucous membranes and increase sus¬ 
ceptibility tO' the invasion of bacterial pathogens already harbored. 

4. Indirect transmission of air-borne respiratory pathogens is tre¬ 
mendously accelerated by rapidly expanding training programs. Dan¬ 
gerous carriers of hemolytic streptococcus are barracked with fresh sus- 
ceptibles. Floors and blankets are heavily contaminated with highly 
pathogenic organisms. Barracks are filled with new trainees as soon as 
billets become empty. Dust and blanket lint containing millions of 
organisms are disseminated with each cleaning of the decks and manipu¬ 
lation of blankets. The rapid turn-over of recruits and the failure to 
recognize the importance of dust control measures permit ideal conditions 
for the inhalation of small numbers of respiratory pathogens by large 
numbers of trainees. If these trainees are recruits, their susceptibility 
is further increased by a coincident lowering of resistance associated 
with acclimatization, changes in living conditions, and reactions to active 
immunizations against tetanus, smallpox, yellow fever, typhus fever, and 
enteric infections. 

5. The indirect transmission of air-borne respiratory bacterial path¬ 
ogens is further accelerated by the passage, directly or indirectly, of cer¬ 
tain viruses. Measles and influenza are air-borne infections dissemi¬ 
nated with facility in crowded barracks. Irrespective of whether an 
individual recruit contracts or escapes these virus infections, there can 
be no doubt that one of the final effects of virus activity in a Naval train- 

155 


ing center is increased pathogenicity of the prevalent strains of hemo¬ 
lytic streptococcus. With increased pathogenicity of this bacterium, the 
morbidity rate rises. The rise is followed by increasing dissemination 
which initiates the epidemic process. 

Theoretically, it is possible to break this circle of spreading contagion, 
because methods are available to control each factor in the initiation and 
perpetuation of a respiratory epidemic. Medical science has almost 
eliminated the explosive outbreaks caused by the ingestion of food infected 
with hemolytic streptococcus. Careful screening out of convalescents be¬ 
fore return to duty and elimination of double-deck bunks will reduce the 
incidence of '‘return cases” in which infection had been directly by the in¬ 
halation of infected droplets. The institution of technics for dust control, 
such as oiling of the decks and blankets in barracks, will reduce the inci¬ 
dence of indirectly transmitted air-borne infections. The cessation of 
instruction in swimming pools will eliminate infections caused by insuffla¬ 
tion. The suppression of measles by passive immunization will remove 
an important virus factor. The protection of a recruit from infection 
during the first 3 weeks of “boot” training, when he is being acclimatized 
and actively immunized, will increase his resistance at the time of max¬ 
imum exposure to hemolytic streptococcus. 

Practically, it is impossible to control all these factors while conducting 
a rapidly expanding training program. The future will undoubtedly 
see the necessary control measures applied in preventive medicine. The 
present must accept the fact that the dissemination and inhalation of 
air-borne respiratory pathogens is not yet controlled by sanitation 
methods in the Navy. The medical officer cannot prevent the seeding 
of micro-organisms; the rooting of these pathogens in the floor dust; the 
transplantation and growth of these infectious agents among his men; 
the branching of this epidemic process to other men in his barracks ; but 
he can now check the fruition of an epidemic process by preventing im¬ 
plantation of respiratory pathogens in susceptible recruits. It was for 
this purpose that the heroic measure of mass chemoprophylaxis was em¬ 
ployed by the U. S. Navy. 

An Appraisal of Mass Chemoprophylaxis 

The present reports, collected in this monograph, clearly indicate the 
effectiveness of mass chemoprophylaxis. Each report represents the 
observations and consensus of several medical officers. The data in¬ 
cluded come from the labors of hundreds of line officers, petty officers, and 
hospital corpsmen. The material was obtained from large Naval training 
activities in all Naval districts of the United States where streptococcal 
infections were prevalent. The design of the prophylactic program was 
blueprinted to meet the needs of these stations with their individual 
respiratory disease problems. The execution of each program varied 

156 




with the size, ability, imagination, and resourcefulness of the individual 
epidemiology unit. The serologic typing of hemolytic streptococcus was 
done under constant conditions in one laboratory. With this exception, 
each report includes variables patently beyond control; nevertheless, given 
one blueprint based on the fact that the presence of sulfadiazine molecules 
on the mucous membranes exerts a bacteriostatic effect on respiratory 
pathogens; given half a million men to protect; given one sulfonamide to 
administer, and given one objective—^given all these factors, medical 
officers report one conclusion: The strategy of mass chemoprophylaxis 
is fundamentally sound. 

The effectiveness of sulfadiazine prophylaxis is shown in these studies 
to be determined in part by the epidemic mechanisms that the drug en¬ 
countered. For example, the pathogenesis of a meningococcal infection 
seems to depend on the spreading of this organism throughout a ‘ffierd’^; 
the pathogenesis of a streptococcal infection seems to depend on implanta¬ 
tion of a virulent strain in the susceptible host; the pathogenesis of a 
pneumococcal pneumonia seems to depend on the lowering of resistance 
of a carrier. The effectiveness of chemoprophylaxis varies accordingly: 

1. Previous observations have indicated that so long as the carrier 
rate of meningococcus is kept low, cerebrospinal fever rarely develops. 
The presence of small amounts of sulfadiazine exerts such a highly bac¬ 
teriostatic effect on meningococcus that the carrier rate is reduced to a 
minimum. Chemoprophylaxis has, therefore, proved to be perfect pro¬ 
tection against cerebrospinal fever in these half million men. 

2. Previous studies have also shown that sulfadiazine,, either in pro¬ 
phylactic or therapeutic dosage, has little effect on the throat flora of car¬ 
riers of hemolytic streptococcus. The present observations have proved 
confirmatory. They showed, moreover, that the presence of small con¬ 
centrations of sulfadiazine in the nasopharyngeal secretions “screens out” 
hemolytic streptococcus. Implantation is prevented in most instances, 
irrespective of the pathogenicity of the prevalent strains; however, in 
some instances, it was shown that organisms penetrated the bacterio¬ 
static effect of sulfadiazine. This occurred after a man had been ingesting 
1 gm. of drug daily for a period of weeks and was maintaining a satis¬ 
factory blood level. This was observed in areas where the exposure to 
streptococcal infections was greatest, and especially among recruits re¬ 
ceiving swimming lessons in the chlorinated water of pools. This oc¬ 
curred most strikingly at the time when the incidence of measles was high. 
There are these undefined conditions that permit hemolytic streptococcus 
to overcome the bacteriostatic effect of small amounts of sulfadiazine. As 
clearly indicated, however, the presence of sulfadiazine in the nasopharyn¬ 
geal secretions usually prevents the implantation of a new strain of hemo¬ 
lytic streptococcus in the throat flora. By this achievement, chemopro¬ 
phylaxis prevents about 95 percent of the frank streptococcal infect’ons 

157 


and about 85 percent of the presumptive streptococcal infections and 
rheumatic fever. 

3. Previous studies have also shown that mechanisms essential for the 
pathogenesis of pneumonia are different from those of meningococcal and 
streptococcal infections. A person may be a carrier of pneumococcus for 
many weeks and escape disease until an episode upsets the host-parasite 
balance in favor of the micro-organism. The present observations show 
that a considerable percentage developed pneumococcal lung infections 
and pneumococcal otitis media while maintaining a sulfadiazine blood 
level of about 2 mg. percent. One factor in the pathogenesis of these 
diseases may have been insufflation occasioned by swimming. Another 
factor, demonstrated in certain instances, was the prevalence of sulfona¬ 
mide-resistant strains of pneumococci. 

4. Previous observations have also indicated that there is variation in 
the resistance of strains of gonococcus to sulfonamides. The present 
studies indicate that in certain areas, especially an:iong Negro recruits, 
chemoprophylaxis was about 95 percent effective and that in other areas, 
it was less effective. Although no effort was made to determine the 
application of small sulfadiazine doses administered on the day following 
exposure, the limited observations suggested that this procedure was 
ineffective. 

Untoward Reactions 

The administration of sulfadiazine prophylaxis to half a million men 
afforded the opportunity to observe most of the untoward drug reactions 
that occur. No renal complications were detected. Most of the reactions 
were dermal; they are described in detail in several of these reports. 
They occurred in about 0.5 percent of Naval trainees during this program. 
Two severe types of reactions, exfoliative dermatitis and granulocytopenia, 
occurred in about 0.01 percent of men receiving prophylaxis. These dan¬ 
gerous manifestations appeared to be reversible unless the patient was 
given therapeutic doses of sulfonamide. Twelve of the fourteen patients 
who died from one of these two diseases are known to have received 
sulfonamide therapy. 

It was observed that a few exhibited drug reactions on the first day of 
prophylaxis. These usually gave a history of having previously exper¬ 
ienced reactions following sulfonamide therapy. Most of che drug reac¬ 
tions developed, however, after a lag period of about 2 weeks, comparable 
to that of serum sickness. A few with severe drug reactions appeared to 
have sulfadiazine fixed in the tissues as evidenced by the recovery of the 
drug from bullae in the skin and in considerable amounts from the blood 
and urine several days after ingestion of the last dose. Although the 
mechanism of these untoward reactions is unknown, the present observa- 

158 


tions suggest that a small percentage of human subjects handle sulfona¬ 
mide m an abnormal manner and become sensitized. They have a drug 
idiosyncrasy and manifest sensitization, irrespective of whether sulfadia¬ 
zine is administered for prophylaxis or treatment. The fact that about 
half of those who had dermal reactions were able to continue prophylaxis 
after a recess of 2 weeks remains unexplained. 

Value of Serologic Identification of Hemolytic Streptococcus 

Careful serologic identification of 5,000 strains of hemolytic strepto¬ 
coccus obtained from 16 training centers has supplied information on 
the epidemic spread of this micro-organism. The results of typing in 
conjunction with clinical observations indicate how variable is the activity 
of any type of hemolytic streptococcus. In the winter and spring months 
of 1944, types 19 and 17 were most injurious to Naval trainees through¬ 
out the United States. The bacteriologic picture differed, however, at 
each of the large training centers and individual variations were observed 
at smaller stations. For example, at a small Maryland activity a severe 
outbreak of streptococcal infections, which precipitated an extraordinarily 
high incidence of rheumatic fever, was caused by types 14 and 3. A 
coincident outbreak at another small activity in Pennsylvania was caused 
by type 30. At Bainbridge, type 19, which had been active in this large 
station since its opening in 1943, remained the predominant strain 
throughout 1944. Type 18, which was rarely recovered elsewhere, was 
second in predominance. In contrast, no type of hemolytic streptococcus 
gained epidemic qualities at the large training stations in Sampson, New 
York, or Davisville, Rhode Island. Furthermore, among the camps of 
the Great Lakes Naval Training Center, there were at least five epidemic 
strains: Types 5, 17, 19, 3, and 1. Type 5, which manifested extensive 
activity at that station, was relatively rare at other stations. Finally, at 
the large training center in Farragut, Idaho', types 17, 19, 1, and 3 were 
epidemic strains. Of these, type 17 showed the greatest virulence for 
man observed in a quarter century and was found to be strikingly sus¬ 
ceptible to sulfadiazine prophylaxis. All four epidemic types at Farragut 
appeared highly communicable. The arrival of Farragut trainees at other 
activities was followed by streptococcal infections and the throat cultures 
at seven centers which received transfer recruits from Farragut revealed 
that the predominant types were 17 or 19 and the second in predominance 
1 or 3. 

Serologic typing of hemolytic streptococcus helped the epidemiologist 
to understand his local problem throughout this program. It was the 
only’available laboratory aid to understanding the transmission of strepto¬ 
coccal diseases throughout camps and from center to center. The 
streptococcal typing of organisms from these half million men clearly 
demonstrated that vagaries in the behavior of this bacterium cannot he 

159 


anticipated. The practical application of information obtained by typing 
must remain limited until technics for immunization prove successful. 

Coincident Virus Infections: A Variable to Be Assessed in 
Mass Chemoprophylaxis 

One of the reasons that makes accurate assessment of mass chemopro¬ 
phylaxis difficult is the unpredictable activity of hemolytic streptococcus. 
A number of factors are recognized as contributory in the evolution of 
epidemic strains of this micro-organism. One of these factors, which is 
perhaps most important in Naval activities, is the prevalence of respir¬ 
atory virus infections. The two most significant are influenza and 
measles viruses. In the Navy it has been possible to record with a fair 
degree of accuracy the activity of measles. The present reports support 
the clinical observations of World War I that the measles virus catalyzes 
the activity of hemolytic streptococcus. During the first 6 months of 
1944, it was observed that in those large training centers where outbreaks 
of streptococcal infections occurred, they were either preceded or accom¬ 
panied by epidemics of measles. Conversely, the large training centers 
that escaped an outbreak of measles, irrespective of the presence or ab¬ 
sence of chemoprophylaxis, also escaped a high morbidity rate from 
streptococcal infections. The following examples illustrate this point: 

1. Four large activities in New York, Rhode Island, North Carolina, 
and Virginia had almost no measles and almost no scarlet fever. 

2. Three large training centers in southern California, Oklahoma, 
and Tennessee experienced contra-seasonal streptococcal epidemics in 
geographic environments where streptococcal diseases were rare. In 
each instance these epidemics either followed or accompanied outbreaks 
of measles. 

3. At one large activity in Idaho the scarlet fever rate was low from 
October 1942 until April 1943. It then rose precipitously for 2 months, 
declined moderately from June to September, then rose moderately, and 
finally hemolytic streptococcus manifested its greatest pathogenicity in 
January of 1944. The initial appearance of the streptococcal process 
occurred at the same time that a measles epidemic of 2 months’ duration 
was subsiding. The second outbreak accompanied an outbreak of in¬ 
fluenza. The final epidemic of most severe streptococcal infections ac¬ 
companied a second outbreak of measles. 

It appeared in these studies that the occurrence of epidemics of measles 
or influenza in areas where hemolytic streptococcus was inactive was 
relatively harmless; but in areas where hemolytic streptococcus was 
already moderately active, these virus outbreaks were accompanied by 
severe streptococcal epidemics. In several instances, there was a lag of 
from 4 to 8 weeks between an outbreak of measles and the manifestations 
of a streptococcal epidemic. With the exception of one small college. 

160 


no streptococcal epidemics occurred at Naval activities in the winter or 
spring of 1944 which were not preceded or accompanied by an outbreak 
of measles. 

These observations indicate that the activity of these two viruses in 
some way reinforces the communicability of hemolytic streptococcus. It 
is impossible to forecast the activity of respiratory viruses. And it is, 
therefore, impossible to predict with accuracy where and when strepto¬ 
coccal epidemics will occur. Whether the extremely low streptococcal 
morbidity rates at two centers can be attributed solely to chemo¬ 
prophylaxis in the absence of measles and influenza during these winter 
months remains to be determined. It is possible, however, to conclude 
from these reports that sulfadiazine is highly effective in preventing the 
implantation of hemolytic streptococcus in the upper respiratory tract of 
susceptible groups of recruits living in camps heavily infected with 
measles and pathogenic strains of hemolytic streptococcus. 

Sulfonamide Resistance of Hemolytic Streptococcus: A Potential Variable 
in the Effectiveness of Mass Prophylaxis 

Sulfadiazine prophylaxis was not 100 percent effective in preventing 
the implantation of hemolytic streptococcus. Some strains were able to 
infect those who had ingested 1 gm. of sulfadiazine daily and who main¬ 
tained a blood level of 2 mg. percent. The explanation for this phenom¬ 
enon is not yet known. It has been suggested that these persons may 
have inhaled a heavy inoculum; may have been infected by direct con¬ 
tact ; may have had a low concentration of sulfadiazine in the secretions 
of the respiratory tract; or may have insufflated during swimming puru¬ 
lent water containing living micro-organisms and cellular debris which 
acted as a sulfonamide inhibitor and afforded protection to the respiratory 
pathogen. These possibilities are real; however, another possibility 
which may be of greater significance is the resistance of the micro-organ¬ 
ism to prophylactic doses of sulfadiazine. 

That no sulfonamide-fast strains were encountered during this program 
is shown by the fact that those who contracted streptococcal infections 
while receiving prophylaxis responded satisfactorily to therapeutic doses 
of sulfadiazine. That sulfonamide resistance did not develop generally 
is shown by the fact that there was no increase in streptococcal morbidity 
throughout 6 months of prophylaxis. The typing results of May 1944, 
suggest, however, that type 19 may have developed resistance to small 
concentrations of sulfadiazine. During this final month of the program, 
type 19 became the predominant organism at several Naval activities. 
At one activity, where all hands received prophylaxis, the predominant 
type disappeared and type 19 was the causative agent in virtually all 
respiratory infections. 


161 


Final solution of this problem has awaited the development of ail 
'‘inhibitor-free” medium which will support normal growth of all strains 
of group A hemolytic streptococcus. Such a medium has recently been 
developed in the Typing Laboratory of the National Medical Center at 
Bethesda, and appropriate studies are now being made to determine 
whether strains recovered after 6 months of prophylaxis are more re¬ 
sistant to sulfadiazine than strains recovered and frozen at the onset of 
this program. A final opinion will be forthcoming with the results of 
these cultural studies. At present, the possibility that some strains of 
group A hemolytic streptococcus are resistant to 1 mg. percent of sulfa¬ 
diazine in the secretions of the respiratory tract seems actual. This may 
well be the most important factor in limiting the effectiveness of sulfa¬ 
diazine prophylaxis in preventing implantation of group A hemolytic 
streptococcus. 

Summary 

1. One cannot estimate accurately the saving in dollars, man-days, or 
lives which results from chemoprophylaxis. 

2. The observations made at eight Naval training centers indicate that 
chemoprophylaxis is 85 percent effective in preventing bacterial infec¬ 
tions of the respiratory tract under conditions favorable to the dissemina¬ 
tion of respiratory pathogens and unfavorable to newly inducted recruits. 

3. In these groups of Naval personnel, a saving of a day per man, per 
month, can be expected when bacterial respiratory pathogens are active. 
If the center’s recruit complement is 30,000 and all hands receive sul¬ 
fadiazine prophylaxis, one can anticipate a saving of 30,000 hospital days 
each month during seasons conducive to respiratory diseases. This is 
equivalent to freeing a 1,000 bed hospital and all the labor and personnel 
associated with the care of the ,sick. 

4. These reports indicate the many assets and the few disadvantages 
of mass chemoprophylaxis. 

These observations are presented by the Bureau of Medicine and 
Surgery of the United States Navy during this period of national crisis 
in the hope that they may prove a help to the Armed Services, an asset 
to the economy of a people at war, and an advance to the progress of 
medicine after the establishment of peace. 

The Division of Preventive Medicine, Brireau of Medicine and Surgery is indebted to Lieuten¬ 
ant (jg) Ethel H, Davis W-V(S)H USNR fbr editorial assistance in Uie preparation of this 
report. 


162 


U. 8. GOVERNMENT PRINTING OFFICE: 1944-599351 




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